Kumar, Sushil, et al.Author Correction: Dll1+ quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway”. Nat Commun 13.1 (2022): , 13, 1, 3927. Web.
Pérez-Núñez, Iván, et al.LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer”. Nat Cancer 33 (2022): , 3, 3, 355-370. Web.Abstract
Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCOR CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC). We unveil an unexpected function of LCOR as a master transcriptional activator of APM genes binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner. Through genetic modification of LCOR expression, we demonstrate its central role in modulation of tumor immunogenicity and ICB responsiveness. In TNBC, LCOR associates with ICB clinical response. Importantly, extracellular vesicle (EV) Lcor-messenger RNA therapy in combination with anti-PD-L1 overcame resistance and eradicated breast cancer metastasis in preclinical models. Collectively, these data support LCOR as a promising target for enhancement of ICB efficacy in TNBC, by boosting of tumor APM independently of IFN.
Tang, Yong, and Yibin Kang. “Microbial metabolite as icebreaker for immunotherapy”. Cell Metab 34.4 (2022): , 34, 4, 506-507. Web.Abstract
Immunotherapy has limited success in triple-negative breast cancer (TNBC). In this issue of Cell Metabolism, Wang et al. found that microbial metabolite TMAO boosts CD8 T cell-mediated antitumor immunity by inducing pyroptosis in tumor cells, enhancing the efficacy of immunotherapy in TNBC (Wang et al., 2022).
Shen, Minhong, et al.Pharmacological disruption of the MTDH-SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer”. Nat Cancer 31 (2022): , 3, 1, 60-74. Web.Abstract
Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH-SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH-SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH-SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer.
Shen, Minhong, et al.Small-molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis”. Nat Cancer 31 (2022): , 3, 1, 43-59. Web.Abstract
Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein-protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.
Meng, Jingjing, et al.Tumor-derived Jagged1 promotes cancer progression through immune evasion”. Cell Rep 38.10 (2022): , 38, 10, 110492. Web.Abstract
Immune checkpoint inhibitor (ICI) therapy is generating remarkable responses in individuals with cancer, but only a small portion of individuals with breast cancer respond well. Here we report that tumor-derived Jagged1 is a key regulator of the tumor immune microenvironment. Jagged1 promotes tumorigenesis in multiple spontaneous mammary tumor models. Through Jagged1-induced Notch activation, tumor cells increase expression and secretion of multiple cytokines to help recruit macrophages into the tumor microenvironment. Educated macrophages crosstalk with tumor-infiltrating T cells to inhibit T cell proliferation and tumoricidal activity. In individuals with triple-negative breast cancer, a high expression level of Jagged1 correlates with increased macrophage infiltration and decreased T cell activity. Co-administration of an ICI PD-1 antibody with a Notch inhibitor significantly inhibits tumor growth in breast cancer models. Our findings establish a distinct signaling cascade by which Jagged1 promotes adaptive immune evasion of tumor cells and provide several possible therapeutic targets.
Fang, Cao, and Yibin Kang. “Cellular plasticity in bone metastasis”. Bone 158 (2022): , 158, 115693. Web.Abstract
Metastasis is responsible for a large majority of death from malignant solid tumors. Bone is one of the most frequently affected organs in cancer metastasis, especially in breast and prostate cancer. Development of bone metastasis requires cancer cells to successfully complete a number of challenging steps, including local invasion and intravasation, survival in circulation, extravasation and initial seeding, and finally, formation of metastatic colonies after a period of dormancy or indolent growth. During this process, cancer cells often undergo a series of cellular and molecular changes to gain cellular plasticity that helps them adapt to various environments they encounter along the journey of metastasis. Understanding the mechanisms behind cellular plasticity and adaptation during the formation of bone metastasis is crucial for the development of novel therapies.
Yang, Jing, et al.Author Correction: Guidelines and definitions for research on epithelial-mesenchymal transition”. Nat Rev Mol Cell Biol 22.12 (2021): , 22, 12, 834. Web.
Chen, Fenfang, Yujiao Han, and Yibin Kang. “Bone marrow niches in the regulation of bone metastasis”. Br J Cancer 124.12 (2021): , 124, 12, 1912-1920. Web.Abstract
The bone marrow has been widely recognised to host a unique microenvironment that facilitates tumour colonisation. Bone metastasis frequently occurs in the late stages of malignant diseases such as breast, prostate and lung cancers. The biology of bone metastasis is determined by tumour-cell-intrinsic traits as well as their interaction with the microenvironment. The bone marrow is a dynamic organ in which various stages of haematopoiesis, osteogenesis, osteolysis and different kinds of immune response are precisely regulated. These different cellular components constitute specialised tissue microenvironments-niches-that play critical roles in controlling tumour cell colonisation, including initial seeding, dormancy and outgrowth. In this review, we will dissect the dynamic nature of the interactions between tumour cells and bone niches. By targeting certain steps of tumour progression and crosstalk with the bone niches, the development of potential therapeutic approaches for the clinical treatment of bone metastasis might be feasible.
Yang, Mu, et al.Changing trends and disparities in 5-year overall survival of women with invasive breast cancer in the United States, 1975-2015”. Am J Cancer Res 11.6 (2021): , 11, 6, 3201-3211. Print.Abstract
Relative survival is the ratio of overall survival (OS) over survival of the general population, and widely used in epidemiological studies. But it is artificially higher than OS and thus inferior to OS for cancer prognostication of individual patients. Moreover, trend-changes and disparities in OS of breast cancer are unclear while the relative survival of breast cancer has been reported on a regular basis. Therefore, we estimated trends in age-standardized 5-year OS of invasive breast cancer, using data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry program and piecewise-linear regression models. Among 188,052 women with breast cancer diagnosed during 2007-2010 (SEER-18, 155,515 [79.3%] survived by year 5), the 5-year OS significantly differed by age, histology, tumor grade, tumor stage, hormone receptors, race/ethnicity, insurance status, region, rural-urban continuum and selected county-attributes. Among 469,498 women with breast cancer diagnosed during 1975-2010 (SEER-9) in the U.S., we observed an upward trend in the age-standardized 5-year OS (stage- and race/ethnicity-adjusted annual percentage change = 0.97 [95% CI, 0.76-1.18]). The 36-year trends/slopes in age-standardized 5-year OS of breast cancer differed by histology, tumor grade, stage, race/ethnicity, region and socioeconomic attributes of the patient's residence-county, but not by those of rural-urban continuum. The 3-joinpoint model on the 36-year trend identified significant slope changes in 1983, 1987 and 2000, with the largest slope (2.5%/year) during 1983-1987. In conclusion, we here show trends in the age-standardized 5-year OS among U.S. women with breast cancer changed in diagnosis-years of 1983, 1987 and 2000, and differed by tumor characteristics and race/ethnicity. More efforts are needed to understand the trend changes and to address the OS disparities of breast cancers.
Kumar, Sushil, et al.Dll1 quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway”. Nat Commun 12.1 (2021): , 12, 1, 432. Web.Abstract
Development of chemoresistance in breast cancer patients greatly increases mortality. Thus, understanding mechanisms underlying breast cancer resistance to chemotherapy is of paramount importance to overcome this clinical challenge. Although activated Notch receptors have been associated with chemoresistance in cancer, the specific Notch ligands and their molecular mechanisms leading to chemoresistance in breast cancer remain elusive. Using conditional knockout and reporter mouse models, we demonstrate that tumor cells expressing the Notch ligand Dll1 is important for tumor growth and metastasis and bear similarities to tumor-initiating cancer cells (TICs) in breast cancer. RNA-seq and ATAC-seq using reporter models and patient data demonstrated that NF-κB activation is downstream of Dll1 and is associated with a chemoresistant phenotype. Finally, pharmacological blocking of Dll1 or NF-κB pathway completely sensitizes Dll1 tumors to chemotherapy, highlighting therapeutic avenues for chemotherapy resistant breast cancer patients in the near future.
Fang, Cao, and Yibin Kang. “E-Cadherin: Context-Dependent Functions of a Quintessential Epithelial Marker in Metastasis”. Cancer Res 81.23 (2021): , 81, 23, 5800-5802. Web.Abstract
Loss of E-cadherin expression has been well known as a hallmark of epithelial-mesenchymal transition (EMT), which is linked to increased risk of cancer metastasis. However, it was less clear whether E-cadherin and its downstream signaling pathways are functionally involved in driving EMT and the prometastatic phenotype. A study by Onder and colleagues in 2008 discovered that E-cadherin loss not only helps tumor cells detach from each other by breaking down cell-cell junctions but also elicits intracellular signaling events to confer a mesenchymal cell state and metastatic phenotype. This study established E-cadherin as an important global regulator, rather than just a marker, of EMT. The discovery inspired further investigation in the following decade that significantly deepened our understanding of E-cadherin and its diverse functions and more broadly of cellular plasticity in different stages and contexts of cancer metastasis..
Kang, Yibin, and Charlotte Kuperwasser. “Evolving barcodes shed light into evolving metastases”. Dev Cell 56.8 (2021): , 56, 8, 1077-1079. Web.Abstract
Selective pressure and signals from the tissue microenvironment drive metastasis and determine the survival of metastatic tumor cells at distant organs. Zhang et al. and Bado et al. apply CRISPR-mediated evolving barcode technology to elucidate the role of the bone microenvironment in the evolution of breast cancer metastasis.
Lee, Eunmi, and Yibin Kang. “Lineage tracing reveals metastatic dynamics”. Cancer Cell 39.8 (2021): , 39, 8, 1050-1052. Web.Abstract
Combining single-cell lineage tracing with RNA sequencing has provided unprecedented opportunities to prospectively explore metastatic dynamics in vivo. In this issue of Cancer Cell, Simeonov et al. developed the macsGESTALT lineage recording system to reveal that hybrid EMT states and S100 expression are associated with elevated metastatic abilities in a pancreatic cancer model.
Spadazzi, Chiara, et al.Trefoil factor-1 upregulation in estrogen-receptor positive breast cancer correlates with an increased risk of bone metastasis”. Bone 144 (2021): , 144, 115775. Web.Abstract
Bone is one of the most preferred sites of metastatic spread from different cancer types, including breast cancer. However, different breast cancer subtypes exhibit distinct metastatic behavior in terms of kinetics and anatomic sites of relapse. Despite advances in the diagnosis, the identification of patients at high-risk of bone recurrence is still an unmet clinical need. We conducted a retrospective analysis, by gene expression and immunohistochemical assays, on 90 surgically resected breast cancer samples collected from patients who experienced no evidence of distant metastasis, bone or visceral metastasis in order to identify a primary tumor-derived marker of bone recurrence. We identified trefoil factor-1 (pS2 or TFF1) as strictly correlated to bone metastasis from ER+ breast cancer. In silico analysis was carried out to confirm this observation, linking gene expression data with clinical characteristics available from public clinical datasets. Then, we investigated TFF1 function in ER+ breast cancer tumorigenesis and bone metastasis through xenograft in vivo models of MCF 7 breast cancer with gain and loss of function of TFF1. As a response to microenvironmental features in primary tumors, TFF1 expression could modulate ER+ breast cancer growth, leading to a less proliferative phenotype. Our results showed it may not play a role in late stages of bone metastasis, however further studies are warranted to understand whether it could contribute in the early-stages of the metastatic cascade. In conclusion, TFF1 upregulation in primary ER+ breast cancer could be useful to identify patients at high-risk of bone metastasis. This could help clinicians in the identification of patients who likely can develop bone metastasis and who could benefit from personalized treatments and follow-up strategies to prevent metastatic disease.
Esposito, Mark, Shridar Ganesan, and Yibin Kang. “Emerging strategies for treating metastasis”. Nat Cancer 23 (2021): , 2, 3, 258-270. Web.Abstract
The systemic spread of tumor cells is the ultimate cause of the majority of deaths from cancer, yet few successful therapeutic strategies have emerged to specifically target metastasis. Here we discuss recent advances in our understanding of tumor-intrinsic pathways driving metastatic colonization and therapeutic resistance, as well as immune activating strategies to target metastatic disease. We focus on therapeutically exploitable mechanisms, promising strategies in preclinical and clinical development, and emerging areas with potential to become innovative treatments.
Song, Kai, et al.Epsins 1 and 2 promote NEMO linear ubiquitination via LUBAC to drive breast cancer development”. J Clin Invest 131.1 (2021). Web.Abstract
Estrogen receptor-negative (ER-negative) breast cancer is thought to be more malignant and devastating than ER-positive breast cancer. ER-negative breast cancer exhibits elevated NF-κB activity, but how this abnormally high NF-κB activity is maintained is poorly understood. The importance of linear ubiquitination, which is generated by the linear ubiquitin chain assembly complex (LUBAC), is increasingly appreciated in NF-κB signaling, which regulates cell activation and death. Here, we showed that epsin proteins, a family of ubiquitin-binding endocytic adaptors, interacted with LUBAC via its ubiquitin-interacting motif and bound LUBAC's bona fide substrate NEMO via its N-terminal homolog (ENTH) domain. Furthermore, epsins promoted NF-κB essential modulator (NEMO) linear ubiquitination and served as scaffolds for recruiting other components of the IκB kinase (IKK) complex, resulting in the heightened IKK activation and sustained NF-κB signaling essential for the development of ER-negative breast cancer. Heightened epsin levels in ER-negative human breast cancer are associated with poor relapse-free survival. We showed that transgenic and pharmacological approaches eliminating epsins potently impeded breast cancer development in both spontaneous and patient-derived xenograft breast cancer mouse models. Our findings established the pivotal role epsins played in promoting breast cancer. Thus, targeting epsins may represent a strategy to restrain NF-κB signaling and provide an important perspective into ER-negative breast cancer treatment.
Esposito, Mark, et al.TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis”. Nat Cell Biol 23.3 (2021): , 23, 3, 257-267. Web.Abstract
The complexity of intracellular signalling requires both a diversity of molecular players and the sequestration of activity to unique compartments within the cell. Recent findings on the role of liquid-liquid phase separation provide a distinct mechanism for the spatial segregation of proteins to regulate signalling pathway crosstalk. Here, we discover that DACT1 is induced by TGFβ and forms protein condensates in the cytoplasm to repress Wnt signalling. These condensates do not localize to any known organelles but, rather, exist as phase-separated proteinaceous cytoplasmic bodies. The deletion of intrinsically disordered domains within the DACT1 protein eliminates its ability to both form protein condensates and suppress Wnt signalling. Isolation and mass spectrometry analysis of these particles revealed a complex of protein machinery that sequesters casein kinase 2-a Wnt pathway activator. We further demonstrate that DACT1 condensates are maintained in vivo and that DACT1 is critical to breast and prostate cancer bone metastasis.
Shen, Minhong, et al.Therapeutic Targeting of Metadherin Suppresses Colorectal and Lung Cancer Progression and Metastasis”. Cancer Res 81.4 (2021): , 81, 4, 1014-1025. Web.Abstract
Colorectal and lung cancers account for one-third of all cancer-related deaths worldwide. Previous studies suggested that metadherin (MTDH) is involved in the development of colorectal and lung cancers. However, how MTDH regulates the pathogenesis of these cancers remains largely unknown. Using genetically modified mouse models of spontaneous colorectal and lung cancers, we found that MTDH promotes cancer progression by facilitating Wnt activation and by inducing cytotoxic T-cell exhaustion, respectively. Moreover, we developed locked nucleic acid-modified (LNA) MTDH antisense oligonucleotides (ASO) that effectively and specifically suppress MTDH expression and . Treatments with MTDH ASOs in mouse models significantly attenuated progression and metastasis of colorectal, lung, and breast cancers. Our study opens a new avenue for developing therapies against colorectal and lung cancers by targeting MTDH using LNA-modified ASO. SIGNIFICANCE: This study provides new insights into the mechanism of MTDH in promoting colorectal and lung cancers, as well as genetic and pharmacologic evidence supporting the development of MTDH-targeting therapeutics.
Fan, Huijuan, et al.ASB13 inhibits breast cancer metastasis through promoting SNAI2 degradation and relieving its transcriptional repression of YAP”. Genes Dev 34.19-20 (2020): , 34, 19-20, 1359-1372. Web.Abstract
Transcription factor SNAI2 plays key roles during development and has also been known to promote metastasis by inducing invasive phenotype and tumor-initiating activity of cancer cells. However, the post-translational regulation of SNAI2 is less well studied. We performed a dual-luciferase-based, genome-wide E3 ligase siRNA library screen and identified ASB13 as an E3 ubiquitin ligase that targets SNAI2 for ubiquitination and degradation. ASB13 knockout in breast cancer cells promoted cell migration and decreased F-actin polymerization, while overexpression of ASB13 suppressed lung metastasis. Furthermore, ASB13 knockout decreased YAP expression, and such regulation is dependent on an increased protein level of SNAI2, which in turn represses YAP transcription. YAP suppresses tumor progression in breast cancer, as YAP knockout increases tumorsphere formation, anchorage-independent colony formation, cell migration in vitro, and lung metastasis in vivo. Clinical data analysis reveals that ASB13 expression is positively correlated with improved overall survival in breast cancer patients. These findings establish ASB13 as a suppressor of breast cancer metastasis by promoting degradation of SNAI2 and relieving its transcriptional repression of YAP.
Aiello-Couzo, Nicole M, and Yibin Kang. “A bridge between melanoma cell states”. Nat Cell Biol 22.8 (2020): , 22, 8, 913-914. Web.
Vrla, Geoffrey D, et al.Cytotoxic alkyl-quinolones mediate surface-induced virulence in Pseudomonas aeruginosa”. PLoS Pathog 16.9 (2020): , 16, 9, e1008867. Web.Abstract
Surface attachment, an early step in the colonization of multiple host environments, activates the virulence of the human pathogen P. aeruginosa. However, the downstream toxins that mediate surface-dependent P. aeruginosa virulence remain unclear, as do the signaling pathways that lead to their activation. Here, we demonstrate that alkyl-quinolone (AQ) secondary metabolites are rapidly induced upon surface association and act directly on host cells to cause cytotoxicity. Surface-induced AQ cytotoxicity is independent of other AQ functions like quorum sensing or PQS-specific activities like iron sequestration. We further show that packaging of AQs in outer-membrane vesicles (OMVs) increases their cytotoxicity to host cells but not their ability to stimulate downstream quorum sensing pathways in bacteria. OMVs lacking AQs are significantly less cytotoxic, suggesting these molecules play a role in OMV cytotoxicity, in addition to their previously characterized role in OMV biogenesis. AQ reporters also enabled us to dissect the signal transduction pathways downstream of the two known regulators of surface-dependent virulence, the quorum sensing receptor, LasR, and the putative mechanosensor, PilY1. Specifically, we show that PilY1 regulates surface-induced AQ production by repressing the AlgR-AlgZ two-component system. AlgR then induces RhlR, which can induce the AQ biosynthesis operon under specific conditions. These findings collectively suggest that the induction of AQs upon surface association is both necessary and sufficient to explain surface-induced P. aeruginosa virulence.
Li, Wenyang, et al.Deubiquitinase USP20 promotes breast cancer metastasis by stabilizing SNAI2”. Genes Dev 34.19-20 (2020): , 34, 19-20, 1310-1315. Web.Abstract
SNAI2/SLUG, a metastasis-promoting transcription factor, is a labile protein that is degraded through the ubiquitin proteasome degradation system. Here, we conducted comprehensive gain- and loss-of-function screens using a human DUB cDNA library of 65 genes and an siRNA library of 98 genes, and identified USP20 as a deubiquitinase (DUB) that regulates SNAI2 ubiquitination and stability. Further investigation of USP20 demonstrated its function in promoting migration, invasion, and metastasis of breast cancer. USP20 positively correlates with SNAI2 protein level in breast tumor samples, and higher USP20 expression is associated with poor prognosis in ER breast cancer patients.
Pham, Kien, et al.E-cigarette promotes breast carcinoma progression and lung metastasis: Macrophage-tumor cells crosstalk and the role of CCL5 and VCAM-1”. Cancer Lett 491 (2020): , 491, 132-145. Web.Abstract
Young women represent a target of E-cigarette (E-cig) companies, raising concern for potential connections with breast cancer (BC) that have not yet been elucidated. We hypothesized that E-cig promotes BC development and lung metastasis possibly through BC-monocyte/tumor-associated macrophage (TAM) crosstalk via CCL5 and V-CAM-1 axes. We demonstrated that E-cig promoted the infiltration of circulating monocytes in mammary fat pad (MFP) model. Furthermore, E-cig exposure significantly enhanced BC cell growth in MFP tumor and metastatic lung colonization; immunohistochemical stains illustrated the increase of TAMs infiltration, reduced BC cell apoptosis and increased proliferation index after E-cig exposure. In vitro studies show E-cig vapor condensate (EVC) treatment upregulated protein expressions of CCL5, V-CAM-1, and other pro-tumorigenic factors in BC cells. Mechanistically, co-culture system demonstrated both EVC and macrophages independently stimulated BC cell growth and the migration via CCL5/CCR1/CCR5 axis. During metastasis, E-Cig exposure stimulated BC cell survival via direct interaction with infiltrated macrophages, regulated by VCAM-1 and integrin αβ1. Our findings, for the first time, showed that E-cig promotes BC growth and metastasis. This study highlights the critical role of TAMs via CCL5 and VCAM-1 pathways in E-cig promoted BC tumor development.
Hoshino, Ayuko, et al.Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers”. Cell 182.4 (2020): , 182, 4, 1044-1061.e18. Web.Abstract
There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.
Ghergurovich, Jonathan M, et al.Glucose-6-Phosphate Dehydrogenase Is Not Essential for K-Ras-Driven Tumor Growth or Metastasis”. Cancer Res 80.18 (2020): , 80, 18, 3820-3829. Web.Abstract
The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a major contributor to NADPH production and redox homeostasis and its expression is upregulated and correlated with negative patient outcomes in multiple human cancer types. Despite these associations, whether G6PD is essential for tumor initiation, growth, or metastasis remains unclear. Here, we employ modern genetic tools to evaluate the role of G6PD in lung, breast, and colon cancer driven by oncogenic K-Ras. Human HCT116 colorectal cancer cells lacking G6PD exhibited metabolic indicators of oxidative stress, but developed into subcutaneous xenografts with growth comparable with that of wild-type controls. In a genetically engineered mouse model of non-small cell lung cancer driven by K-Ras G12D and p53 deficiency, G6PD knockout did not block formation or proliferation of primary lung tumors. In MDA-MB-231-derived human triple-negative breast cancer cells implanted as orthotopic xenografts, loss of G6PD modestly decreased primary site growth without ablating spontaneous metastasis to the lung and moderately impaired the ability of breast cancer cells to colonize the lung when delivered via tail vein injection. Thus, in the studied K-Ras tumor models, G6PD was not strictly essential for tumorigenesis and at most modestly promoted disease progression. SIGNIFICANCE: K-Ras-driven tumors can grow and metastasize even in the absence of the oxidative pentose pathway, a main NADPH production route.
Yang, Jing, et al.Guidelines and definitions for research on epithelial-mesenchymal transition”. Nat Rev Mol Cell Biol 21.6 (2020): , 21, 6, 341-352. Web.Abstract
Epithelial-mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and invasion. EMT occurs in a diverse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by 'the EMT International Association' (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining diversity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT.
Lu, Wei, and Yibin Kang. “Epithelial-Mesenchymal Plasticity in Cancer Progression and Metastasis”. Dev Cell 49.3 (2019): , 49, 3, 361-374. Web.Abstract
Epithelial-to-mesenchymal transition (EMT) and its reversed process, mesenchymal-to-epithelial transition (MET), are fundamental processes in embryonic development and tissue repair but confer malignant properties to carcinoma cells, including invasive behavior, cancer stem cell activity, and greater resistance to chemotherapy and immunotherapy. Understanding the molecular and cellular basis of EMT provides fundamental insights into the etiology of cancer and may, in the long run, lead to new therapeutic strategies. Here, we discuss the regulatory mechanisms and pathological roles of epithelial-mesenchymal plasticity, with a focus on recent insights into the complexity and dynamics of this phenomenon in cancer.
Shen, Minhong, and Yibin Kang. “Role Reversal: A Pro-metastatic Function of E-Cadherin”. Dev Cell 51.4 (2019): , 51, 4, 417-419. Web.Abstract
Carcinoma cells often acquire mobility and invasiveness by undergoing epithelial-to-mesenchymal transition, and yet most metastatic lesions remain epithelial in nature. Recently, in Nature, Padmanaban et al. (2019) demonstrated that the quintessential epithelial marker E-cadherin promotes metastasis of invasive ductal breast carcinoma by enhancing the survival of tumor cells.
C, Liverani, and et al. “A biomimetic 3D model of hypoxia-driven cancer progression.”. Science Reports, a Nature Research Journal 9 (2019). Web. Pub Med
Board Members, Metastasis Research Society. “The importance of developing therapies targeting the biological spectrum of metastatic disease.”. Clinical & Experimental Metastasis 36 (2019). Web. Pub Med
M, Esposito, and et al. “Bone vascular niche E-selectin induces mesenchymal-epithelial transition and Wnt activation in cancer cells to promote bone metastasis.”. Nat Cell Biol 21 (2019). Web. Pub Med
Aiello NM, Kang Y.Context-dependent EMT programs in cancer metastasis.”. Journal of Experimental Medicine (2019). Web. Pub Med
Lu, S, and et al. “Racial profiling harms science.”. Science 363 (2019). Web. Pub Med
T, Celià-Terrassa. “Author Correction: Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability.”. 10 (2019). Web. Pub MedAbstract
The original version of this Article contained an error in the spelling of the author Daniel D. Liu, which was incorrectly given as Daniel Liu. This has now been corrected in both the PDF and HTML versions of the Article.
H, Zhang, and et al. “CD44 splice isoform switching determines breast cancer stem cell state.”. Genes Dev 33 (2019). Web. Pub Med
Monsivais D,, et al.Activin-like kinase 5 (ALK5) inactivation in the mouse uterus results in metastatic endometrial carcinoma.”. Proc Natl Acad Sci 116 (2019). Web. Pub Med
W, Zhuo, and et al. “Long Noncoding RNA GMAN, Up-regulated in Gastric Cancer Tissues, Is Associated With Metastasis in Patients and Promotes Translation of Ephrin A1 by Competitively Binding GMAN-AS”. Gastroenterology 156.3 (2019). Web. Pub Med
M, Shen, and “Tinagl1 Suppresses Triple-Negative Breast Cancer Progression and Metastasis by Simultaneously Inhibiting Integrin/FAK and EGFR Signaling.”. Cancer Cell 35 (2019). Web. Pub Med
T, Celià-Terrassa, et al.Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability.”. Nat Commununications 9 (2018). Web. Pub Med
Shen M, Kang Y.Complex interplay between tumor microenvironment and cancer therapy.”. Frontiers of Medicine 12 (2018). Web. Pub Med
Celià-Terrassa T, Kang Y.Metastatic niche functions and therapeutic opportunities.”. Nat Cell Biol 20 (2018). Web. Pub Med
R, Chakrabarti, et al.Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche.”. Science 360.6396 (2018). Web. Pub Med
Jin, Lingtao, et al.The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer”. Mol Cell 69.1 (2018): , 69, 1, 87-99.e7. Web. Pub MedAbstract
Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents is in its infancy. Here we report that a glutaminolytic enzyme, glutamate dehydrogenase 1 (GDH1), upregulated upon detachment via pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro-metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product α-KG activates CamKK2 by enhancing its substrate AMPK binding, which contributes to energy production that confers anoikis resistance. The effect of GDH1 on AMPK is evident in LKB1-deficient lung cancer, where AMPK activation predominantly depends on CamKK2. Targeting GDH1 with R162 attenuated tumor metastasis in patient-derived xenograft model and correlation studies in lung cancer patients further validated the clinical relevance of our finding. Our study provides insight into the molecular mechanism by which GDH1-mediated metabolic reprogramming of glutaminolysis mediates lung cancer metastasis and offers a therapeutic strategy for patients with LKB1-deficient lung cancer.
Oslund, Rob C, et al.Bisphosphoglycerate mutase controls serine pathway flux via 3-phosphoglycerate”. Nat Chem Biol 13.10 (2017): , 13, 10, 1081-1087. Web.Abstract
Lower glycolysis involves a series of reversible reactions, which interconvert intermediates that also feed anabolic pathways. 3-phosphoglycerate (3-PG) is an abundant lower glycolytic intermediate that feeds serine biosynthesis via the enzyme phosphoglycerate dehydrogenase, which is genomically amplified in several cancers. Phosphoglycerate mutase 1 (PGAM1) catalyzes the isomerization of 3-PG into the downstream glycolytic intermediate 2-phosphoglycerate (2-PG). PGAM1 needs to be histidine phosphorylated to become catalytically active. We show that the primary PGAM1 histidine phosphate donor is 2,3-bisphosphoglycerate (2,3-BPG), which is made from the glycolytic intermediate 1,3-bisphosphoglycerate (1,3-BPG) by bisphosphoglycerate mutase (BPGM). When BPGM is knocked out, 1,3-BPG can directly phosphorylate PGAM1. In this case, PGAM1 phosphorylation and activity are decreased, but nevertheless sufficient to maintain normal glycolytic flux and cellular growth rate. 3-PG, however, accumulates, leading to increased serine synthesis. Thus, one biological function of BPGM is controlling glycolytic intermediate levels and thereby serine biosynthetic flux.
Peng, Jia, and Yibin Kang. “The Bony Side of Endothelial Cells in Prostate Cancer”. Dev Cell 41.5 (2017): , 41, 5, 451-452. Web.Abstract
Prostate cancer bone metastases are primarily osteoblastic, but the source of bone-forming cells in these lesions remains poorly defined. In this issue of Developmental Cell, Lin et al. (2017) demonstrate that tumor-associated endothelial cells can give rise to osteoblasts in prostate cancer through endothelial-to-osteoblast (EC-to-OSB) conversion.
Alečković, Maša, et al.Identification of Nidogen 1 as a lung metastasis protein through secretome analysis”. Genes Dev 31.14 (2017): , 31, 14, 1439-1455. Web.Abstract
Secreted proteins play crucial roles in mediating tumor-stroma interactions during metastasis of cancer to different target organs. To comprehensively profile secreted proteins involved in lung metastasis, we applied quantitative mass spectrometry-based proteomics and identified 392 breast cancer-derived and 302 melanoma-derived proteins secreted from highly lung metastatic cells. The cancer-specific lung metastasis secretome signatures (LMSSs) displayed significant prognostic value in multiple cancer clinical data sets. Moreover, we observed a significant overlap of enriched pathways between the LMSSs of breast cancer and melanoma despite an overall small overlap of specific proteins, suggesting that common biological processes are executed by different proteins to enable the two cancer types to metastasize to the lung. Among the novel candidate lung metastasis proteins, Nidogen 1 (NID1) was confirmed to promote lung metastasis of breast cancer and melanoma, and its expression is correlated with poor clinical outcomes. In vitro functional analysis further revealed multiple prometastatic functions of NID1, including enhancing cancer cell migration and invasion, promoting adhesion to the endothelium and disrupting its integrity, and improving vascular tube formation capacity. As a secreted prometastatic protein, NID1 may be developed as a new biomarker for disease progression and therapeutic target in breast cancer and melanoma.
Celià-Terrassa, Toni, et al.Normal and cancerous mammary stem cells evade interferon-induced constraint through the miR-199a-LCOR axis”. Nat Cell Biol 19.6 (2017): , 19, 6, 711-723. Web.Abstract
Tumour-initiating cells, or cancer stem cells (CSCs), possess stem-cell-like properties observed in normal adult tissue stem cells. Normal and cancerous stem cells may therefore share regulatory mechanisms for maintaining self-renewing capacity and resisting differentiation elicited by cell-intrinsic or microenvironmental cues. Here, we show that miR-199a promotes stem cell properties in mammary stem cells and breast CSCs by directly repressing nuclear receptor corepressor LCOR, which primes interferon (IFN) responses. Elevated miR-199a expression in stem-cell-enriched populations protects normal and malignant stem-like cells from differentiation and senescence induced by IFNs that are produced by epithelial and immune cells in the mammary gland. Importantly, the miR-199a-LCOR-IFN axis is activated in poorly differentiated ERbreast tumours, functionally promotes tumour initiation and metastasis, and is associated with poor clinical outcome. Our study therefore reveals a common mechanism shared by normal and malignant stem cells to protect them from suppressive immune cytokine signalling.
Yang, Mu, et al.Short-term and long-term clinical outcomes of uncommon types of invasive breast cancer”. Histopathology 71.6 (2017): , 71, 6, 874-886. Web.Abstract
AIMS: Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are predominant and well-documented types of invasive breast cancer (IBC). We investigated the clinical outcomes of other types of IBC (i.e. uncommon IBC), which collectively account for Σ20% of all IBC cases, as these are largely unknown. METHODS AND RESULTS: We identified all IBC cases diagnosed in 2004-2006 (n = 159 293) and 2010-2011 (n = 118 822) from the Surveillance, Epidemiology and End Results (SEER) database. Uncommon IBCs included mixed IDC and ILC (MDLC), IDC mixed with other types of carcinoma, ILC mixed with other types of carcinoma, and other-type breast cancers (OCs). We estimated overall survival (OS) and cancer-specific survival in multivariate regression models. As compared with IDC, MDLC was associated with an increased OS [adjusted hazard ratio (aHR) = 0.92, P < 0.001 at Σ10 years of follow-up; aHR = 0.88, P = 0.01 at Σ4 years of follow-up], whereas OCs were associated with a decreased OS (aHR = 1.06, P = 0.005 at Σ10 years of follow-up; aHR = 1.23, P < 0.001 at Σ4 years of follow-up). Women with other uncommon IBCs had an OS similar to those with IDC. Heterogeneity in survival was observed for some subtypes of OC, with better OS for women with MDLC and tubular carcinoma. Radiotherapy extended OS for all types of IBC in older women (≥50 years). For younger women (<50 years), radiotherapy improved OS in women with IDC, but not in those with ILC or uncommon IBC. Radiotherapy did not change cancer-specific survival of younger women with any IBC. CONCLUSIONS: Uncommon IBCs have distinct patterns of prognosis and survival. The effectiveness of radiotherapy in women with uncommon IBC may differ by age. The underlying mechanisms warrant further studies.
Lu, Yi, et al.Twa1/Gid8 is a β-catenin nuclear retention factor in Wnt signaling and colorectal tumorigenesis”. Cell Res 27.12 (2017): , 27, 12, 1422-1440. Web.Abstract
Hyperactivation of Wnt/β-catenin signaling is one of the major causes of human colorectal cancer (CRC). A hallmark of Wnt signaling is the nuclear accumulation of β-catenin. Although β-catenin nuclear import and export have been widely investigated, the underlying mechanism of β-catenin's nuclear retention remains largely unknown. Here, we report that Twa1/Gid8 is a key nuclear retention factor for β-catenin during Wnt signaling and colorectal carcinogenesis. In the absence of Wnt, Twa1 exists together with β-catenin in the Axin complex and undergoes ubiquitination and degradation. Upon Wnt signaling, Twa1 translocates into the nucleus, where it binds and retains β-catenin. Depletion of Twa1 attenuates Wnt-stimulated gene expression, dorsal development of zebrafish embryos and xenograft tumor growth of CRC cells. Moreover, nuclear Twa1 is significantly upregulated in human CRC tissues, correlating with the nuclear accumulation of β-catenin and poor prognosis. Thus, our results identify Twa1 as a previously undescribed regulator of the Wnt pathway for promoting colorectal tumorigenesis by facilitating β-catenin nuclear retention.
Ye, Xin, et al.Upholding a role for EMT in breast cancer metastasis”. Nature 547.7661 (2017): , 547, 7661, E1-E3. Web.
Aiello, Nicole M, et al.Upholding a role for EMT in pancreatic cancer metastasis”. Nature 547.7661 (2017): , 547, 7661, E7-E8. Web.
Zheng, Hanqiu, et al.Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy”. Cancer Cell 32.6 (2017): , 32, 6, 731-747.e6. Web.Abstract
Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (clone 15D11). In addition to its inhibitory effect on bone metastasis of Jagged1-expressing tumor cells, 15D11 dramatically sensitizes bone metastasis to chemotherapy, which induces Jagged1 expression in osteoblasts to provide a survival niche for cancer cells. We further confirm the bone metastasis-promoting function of osteoblast-derived Jagged1 using osteoblast-specific Jagged1 transgenic mouse model. These findings establish 15D11 as a potential therapeutic agent for the prevention or treatment of bone metastasis.
Esposito, Mark, Theresa Guise, and Yibin Kang. “The Biology of Bone Metastasis”. Cold Spring Harb Perspect Med (2017). Web.Abstract
Bone metastasis, or the development of secondary tumors within the bone of cancer patients, is a debilitating and incurable disease. Despite its morbidity, the biology of bone metastasis represents one of the most complex and intriguing of all oncogenic processes. This complexity derives from the intricately organized bone microenvironment in which the various stages of hematopoiesis, osteogenesis, and osteolysis are jointly regulated but spatially restricted. Disseminated tumor cells (DTCs) from various common malignancies such as breast, prostate, lung, and kidney cancers or myeloma are uniquely primed to subvert these endogenous bone stromal elements to grow into pathological osteolytic or osteoblastic lesions. This colonization process can be separated into three key steps: seeding, dormancy, and outgrowth. Targeting the processes of dormancy and initial outgrowth offers the most therapeutic promise. Here, we discuss the concepts of the bone metastasis niche, from controlling tumor-cell survival to growth into clinically detectable disease.
Sánchez-Cid, Lourdes, et al.MicroRNA-200, associated with metastatic breast cancer, promotes traits of mammary luminal progenitor cells”. Oncotarget 848 (2017): , 8, 48, 83384-83406. Web.Abstract
MicroRNAs are critical regulators of gene networks in normal and abnormal biological processes. Focusing on invasive ductal breast cancer (IDC), we have found dysregulated expression in tumor samples of several microRNAs, including the miR-200 family, along progression from primary tumors to distant metastases, further reflected in higher blood levels of miR-200b and miR-7 in IDC patients with regional or distant metastases relative to patients with primary node-negative tumors. Forced expression of miR-200s in MCF10CA1h mammary cells induced an enhanced epithelial program, aldehyde dehydrogenase (ALDH) activity, mammosphere growth and ability to form branched tubuloalveolar structures while promoting orthotopic tumor growth and lung colonization. MiR-200s also induced the constitutive activation of the PI3K-Akt signaling through downregulation of PTEN, and the enhanced mammosphere growth and ALDH activity induced in MCF10CA1h cells by miR-200s required the activation of this signaling pathway. Interestingly, the morphology of tumors formedby cells expressing miR-200s was reminiscent of metaplastic breast cancer (MBC). Indeed, the epithelial components of MBC samples expressed significantly higher levels of miR-200s than their mesenchymal components and displayed a marker profile compatible with luminal progenitor cells. We propose that microRNAs of the miR-200 family promote traits of highly proliferative breast luminal progenitor cells, thereby exacerbating the growth and metastatic properties of transformed mammary epithelial cells.
Liu, Daniel D, and Yibin Kang. “Ets2 anchors the prometastatic function of mutant p53 in osteosarcoma”. Genes Dev 31.18 (2017): , 31, 18, 1823-1824. Web.Abstract
Mutations in the tumor suppressor p53 occur in a majority of human cancers. Some gain-of-function (GOF) p53 mutations endow tumor cells with increased metastatic ability, although our understanding of the underlying mechanism remains incomplete. In this issue of, Pourebrahim and colleagues (pp. 1847-1857) develop a new mouse model of osteosarcoma in which a GOF mutant p53 allele is expressed specifically in osteoblasts, while the tumor microenvironment remains wild type for p53, allowing for the study of cell-autonomous functions. In this model, the role of GOF mutant p53 in promoting lung metastasis is shown to be critically dependent on the transcription factor Ets2 and is accompanied by the elevated expression of a cluster of small nucleolar RNAs (snoRNAs).
Li, Zhuo, and Yibin Kang. “Lipid Metabolism Fuels Cancer's Spread.”. Cell Metab 25.2 (2017): , 25, 2, 228-230. Web.Abstract
The ability to prospectively identify metastasis-initiating cells is essential for developing new anti-metastasis therapeutics. In a recent issue of Nature, Pascual et al. (2017) demonstrate that the fatty acid receptor CD36 marks a subpopulation of cancer cells with unique metastasis-initiating potential, highlighting a key role of lipid metabolism in metastatic colonization.
Zhuo, Wei, and Yibin Kang. “Lnc-ing ROR1-HER3 and Hippo signalling in metastasis.”. Nat Cell Biol 19.2 (2017): , 19, 2, 81-83. Web.Abstract
Long noncoding RNAs (lncRNAs) are increasingly recognized for their role in cancer progression. The previously uncharacterized lncRNA MAYA is now shown to promote bone metastasis by bridging ROR1-HER3 and Hippo-YAP pathways. Neuregulin-induced HER3 phosphorylation by ROR1 recruits a MAYA-containing protein complex to methylate Hippo/MST1 and activate YAP target genes that are essential for bone metastasis.
Celià-Terrassa, Toni, and Yibin Kang. “Mouse genomic screen reveals novel host regulator of metastasis”. Genome Biol 18.1 (2017): , 18, 1, 31. Web.Abstract
Tumor cells have to overcome challenges in the host tissue microenvironment to metastasize successfully to distant organs. In a recent Nature study, a genome-wide functional screen demonstrated that deficiency of the sphingosine-1-phoshate (S1P) transporter gene Spns2 in endothelium increased immune-mediated cell killing by T cells and natural killer (NK) cells, thereby suppressing metastatic colonization.
Peinado, Héctor, et al.Pre-metastatic niches: organ-specific homes for metastases.”. Nat Rev Cancer 17.5 (2017): , 17, 5, 302-317. Web.Abstract
It is well established that organs of future metastasis are not passive receivers of circulating tumour cells, but are instead selectively and actively modified by the primary tumour before metastatic spread has even occurred. Sowing the 'seeds' of metastasis requires the action of tumour-secreted factors and tumour-shed extracellular vesicles that enable the 'soil' at distant metastatic sites to encourage the outgrowth of incoming cancer cells. In this Review, we summarize the main processes and new mechanisms involved in the formation of the pre-metastatic niche.
Shirvani-Dastgerdi, Elham, et al.Selection of the highly replicative and partially multidrug resistant rtS78T HBV polymerase mutation during TDF-ETV combination therapy.”. J Hepatol (2017). Web.Abstract
BACKGROUND & AIMS: Patients chronically infected with the hepatitis B virus (HBV) and receiving long-term treatment with nucleoside or nucleotide analogues are at risk of selecting HBV strains with complex mutational patterns. We herein report two cases of HBV-infected patients with insufficient viral suppression, despite dual antiviral therapy with entecavir (ETV) and tenofovir (TDF). One patient died from aggressive hepatocellular carcinoma (HCC). METHODS: Serum samples from the two patients at different time points were analyzed using ultra-deep pyrosequencing analysis. HBV mutations were identified and transiently transfected into hepatoma cells in vitro using replication-competent HBV vectors, and functionally analyzed. We assessed replication efficacy, resistance to antivirals and potential impact on HBV secretion (viral particles, exosomes). RESULTS: Sequencing analyses revealed the selection of the rtS78T HBV polymerase mutation in both cases that simultaneously creates a premature stop codon at sC69 and thereby deletes almost the entire small HBV surface protein. One of the patients had an additional 261bp deletion in the preS1/S2 region. Functional analyses of the mutations in vitro revealed that the rtS78T/sC69∗ mutation, but not the preS1/S2 deletion, significantly enhanced viral replication and conferred reduced susceptibility to ETV and TDF. The sC69∗ mutation caused truncation of HBs protein, leading to impaired detection by commercial HBsAg assay, without causing intracellular HBsAg retention or affecting HBV secretion. CONCLUSIONS: The rtS78T/sC69∗ HBV mutation, associated with enhanced replication and insufficient response to antiviral treatment, may favor long-term persistence of these isolates. In addition to the increased production of HBV transcripts and the sustained secretion of viral particles in the absence of antigenic domains of S protein, this HBV mutation may predispose patients to carcinogenic effects. LAY SUMMARY: Long-term treatment with antiviral drugs carries the risk of selecting mutations in the hepatitis B virus (HBV). We herein report two cases of patients with insufficient response to dual tenofovir and entecavir therapy. Molecular analyses identified a distinct mutation, rtS78T/sC69∗, that abolishes HBsAg detection, enhances replication, sustains exosome-mediated virion secretion and decreases susceptibility to antivirals, thereby representing a potentially high-risk mutation for HBV-infected individuals.
Zheng, Hanqiu, Wenyang Li, and Yibin Kang. “Tumor-Stroma Interactions in Bone Metastasis: Molecular Mechanisms and Therapeutic Implications.”. Cold Spring Harb Symp Quant Biol (2017). Web.Abstract
Metastasis and associated complications are the major cause of death for cancer patients. The incidence of bone metastasis is among the highest in cancers arising from breast, prostate, and lung. Common skeletal-related events caused by bone metastasis include aberrant bone remodeling (osteolytic, osteoblastic, and mixed), bone pain, fracture, spinal cord compression, and life-threatening hypercalcemia. It is now known that interactions between tumor cells and bone stroma lie at the core of major steps of bone-metastasis progression. Approved pharmaceutical drugs for the treatment of bone metastasis, including bisphosphonate and denosumab, were designed to target bone stromal cell components. In recent years, research in our laboratory and others has revealed intricate tumor-stroma interactions as the driving force behind osteolytic bone-metastasis development, providing a set of new candidates for future drug development. Moreover, recent studies also indicate existence of distinct bone niches in supporting hematopoietic stem cell renewal and differentiation. These niche components are likely utilized by metastatic cancer cells for seeding, progression, and therapy resistance of bone metastasis. Future studies in this direction may discover additional therapeutic targets for bone-metastasis treatment.
Kang, Yibin. “Imaging TGFβ Signaling in Mouse Models of Cancer Metastasis.”. Methods Mol Biol 1344 (2016): , 1344, 219-32. Web.Abstract
Metastatic spread of cancer cells from the primary tumors to distant vital organs, such as lung, liver, brain, and bone, is responsible for the majority of cancer-related deaths. Development of metastatic lesions is critically dependent on the interaction of tumor cells with the stromal microenvironment. As a multifunctional paracrine signaling factor that is abundantly produced by both tumor and stromal cells, TGFβ has been well established as an important mediator of tumor-stromal interaction during cancer metastasis. Imaging the in vivo dynamic of TGFβ signaling activity during cancer metastasis is critical for understanding the pathogenesis of the disease, and for the development of effective anti-metastasis treatments. In this chapter, I describe several xenograft methods to introduce human breast cancer cells into nude mice in order to generate spontaneous and experimental metastases, as well as the luciferase-based bioluminescence imaging method for quantitative imaging analysis of TGFβ signaling in tumor cells during metastasis.
Zhao, Pu, et al.The CD44s splice isoform is a central mediator for invadopodia activity.”. J Cell Sci 129.7 (2016): , 129, 7, 1355-65. Web.Abstract
The ability for tumor cells to spread and metastasize to distant organs requires proteolytic degradation of extracellular matrix (ECM). This activity is mediated by invadopodia, actin-rich membrane protrusions that are enriched for proteases. However, the mechanisms underlying invadopodia activity are not fully understood. Here, we report that a specific CD44 splice isoform, CD44s, is an integral component in invadopodia. We show that CD44s, but not another splice isoform CD44v, is localized in invadopodia. Small hairpin (sh)RNA-mediated depletion of CD44s abolishes invadopodia activity, prevents matrix degradation and decreases tumor cell invasiveness. Our results suggest that CD44s promotes cortactin phosphorylation and recruits MT1-MMP (also known as MMP14) to sites of matrix degradation, which are important activities for invadopodia function. Importantly, we show that depletion of CD44s inhibits breast cancer cell metastasis to the lung in animals. These findings suggest a crucial mechanism underlying the role of the CD44s splice isoform in breast cancer metastasis.
Kang, Yibin. “Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis.”. Endocrinol Metab (Seoul) 31.2 (2016): , 31, 2, 206-12. Web.Abstract
Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients with severe complications such as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolytic bone metastasis depends on cross-communications between tumor cells and various stromal cells residing in the bone microenvironment. Several growth factor signaling pathways, secreted micro RNAs (miRNAs) and exosomes are functional mediators of tumor-stromal interactions in bone metastasis. We developed a functional genomic approach to systemically identified molecular pathways utilized by breast cancer cells to engage the bone stroma in order to generate osteolytic bone metastasis. We showed that elevated expression of vascular cell adhesion molecule 1 (VCAM1) in disseminated breast tumor cells mediates the recruitment of pre-osteoclasts and promotes their differentiation to mature osteoclasts during the bone metastasis formation. Transforming growth factor β (TGF-β) is released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGF-β target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. Substantially change in miRNA expression was observed in osteoclasts during their differentiation and maturation, which can be exploited as circulating biomarkers of emerging bone metastasis and therapeutic targets for the treatment of bone metastasis. Further research in this direction may lead to improved diagnosis and treatment strategies for bone metastasis.
Celià-Terrassa, Toni, and Yibin Kang. “Distinctive properties of metastasis-initiating cells.”. Genes Dev 30.8 (2016): , 30, 8, 892-908. Web.Abstract
Primary tumors are known to constantly shed a large number of cancer cells into systemic dissemination, yet only a tiny fraction of these cells is capable of forming overt metastases. The tremendous rate of attrition during the process of metastasis implicates the existence of a rare and unique population of metastasis-initiating cells (MICs). MICs possess advantageous traits that may originate in the primary tumor but continue to evolve during dissemination and colonization, including cellular plasticity, metabolic reprogramming, the ability to enter and exit dormancy, resistance to apoptosis, immune evasion, and co-option of other tumor and stromal cells. Better understanding of the molecular and cellular hallmarks of MICs will facilitate the development and deployment of novel therapeutic strategies.
Li, Zhuo, and Yibin Kang. “Emerging therapeutic targets in metastatic progression: A focus on breast cancer.”. Pharmacol Ther 161 (2016): , 161, 79-96. Web.Abstract
Metastasis is the underlying cause of death for the majority of breast cancer patients. Despite significant advances in recent years in basic research and clinical development, therapies that specifically target metastatic breast cancer remain inadequate, and represents the single greatest obstacle to reducing mortality of late-stage breast cancer. Recent efforts have leveraged genomic analysis of breast cancer and molecular dissection of tumor-stromal cross-talk to uncover a number of promising candidates for targeted treatment of metastatic breast cancer. Rational combinations of therapeutic agents targeting tumor-intrinsic properties and microenvironmental components provide a promising strategy to develop precision treatments with higher specificity and less toxicity. In this review, we discuss the emerging therapeutic targets in breast cancer metastasis, from tumor-intrinsic pathways to those that involve the host tissue components, including the immune system.
Kang, Yibin, et al.A Five-Species Jungle Game.”. PLoS One 11.6 (2016): , 11, 6, e0157938. Web.Abstract
In this paper, we investigate the five-species Jungle game in the framework of evolutionary game theory. We address the coexistence and biodiversity of the system using mean-field theory and Monte Carlo simulations. Then, we find that the inhibition from the bottom-level species to the top-level species can be critical factors that affect biodiversity, no matter how it is distributed, whether homogeneously well mixed or structured. We also find that predators' different preferences for food affect species' coexistence.
Hu, Jing-Ye, et al.MicroRNA-711 is a prognostic factor for poor overall survival and has an oncogenic role in breast cancer.”. Oncol Lett 11.3 (2016): , 11, 3, 2155-2163. Web.Abstract
MicroRNAs are important in cancer development and progression. In the present study, the clinical significance and function of microRNA-711 (miR-711) expression in breast cancer were investigated. The expression level of miR-711 was analyzed in breast cancer tissue samples using reverse transcription-quantitative polymerase chain reaction. Cell proliferation, colony formation, apoptosis and Transwell assays were performed in breast cancer cell lines transfected with miR-711 mimics or inhibitors, or control sequence. miR-711 was found to be upregulated in 30 formalin-fixed paraffin-embedded breast cancer tissue samples compared with paired non-cancerous breast tissues (P<0.05). Furthermore, a higher miR-711 expression was demonstrated to be associated with poor overall and disease-free survival times in 161 breast cancer patients, and miR-711 was identified as an independent prognostic factor using multivariate Cox regression analysis. In vitro, overexpression of miR-711 resulted in a significant increase in proliferation, colony formation, migration and invasion of breast cancer cells. By contrast, downregulating miR-711 inhibited cell proliferation, colony formation, migration and invasion and enhanced the rate of apoptosis of breast cancer cells. To the best of our knowledge, the present study is the first to demonstrate that miR-711 is an independent prognostic factor and serves an important oncogenic function in breast cancer, suggesting that miR-711 is a potential biomarker of prognosis and a molecular therapeutic target in breast cancer.
Bednarz-Knoll, Natalia, et al.Potential Involvement of Jagged1 in Metastatic Progression of Human Breast Carcinomas.”. Clin Chem 62.2 (2016): , 62, 2, 378-86. Web.Abstract
BACKGROUND: Jagged1, the ligand of Notch, has been shown to be involved in formation of bone metastases in an experimental study. Here, clinical relevance of Jagged1 expression in tumor progression was assessed in human breast carcinomas. METHODS: Jagged1 expression was evaluated by immunohistochemistry in 228 tumor tissue samples and compared to clinicopathologic parameters and patients' outcomes. Furthermore, circulating tumor cells (CTCs) from peripheral blood of 100 unmatched metastatic cancer patients with progressive disease were enriched using Ficoll density gradient centrifugation and detected by pan-keratin/Jagged1/CD45 immunofluorescent staining. RESULTS: Jagged1 expression was detected in 50% of 228 tumors. Jagged1 expression was correlated with higher tumor grade (P = 0.047), vascular invasion (P = 0.026), luminal B subtype (P = 0.016), overexpression of Her-2 (P = 0.001), high Ki-67 expression (P = 0.035), and aldehyde dehydrogenase 1 (ALDH1) positivity (P = 0.013). Jagged 1 expression indicated shorter disease-free survival (DFS) (P = 0.040) and metastasis-free survival (P = 0.048) in lymph node-negative breast cancer for which it was the only independent predictor of DFS (multivariate analysis, P = 0.046). Tumors characterized by the strongest Jagged1 staining intensity (7.5% of cases) correlated with lymph node positivity (P = 0.037), metastatic relapse (P = 0.049), and higher number of disseminated tumor cells in bone marrow aspirates (P = 0.041). Twenty-one unmatched metastatic breast cancer patients with progressive disease were positive for CTCs, and 85.7% of the CTCs also expressed Jagged1. The presence of Jagged1(+) CTCs was significantly associated with shorter progression-free survival in patients treated with bisphosphonates (P = 0.013). CONCLUSIONS: Jagged1 expression characterizes more aggressive breast carcinoma and might be involved in tumor cell dissemination, metastatic progression, and resistance to bone-targeting therapy in breast cancer patients.
Li, Wenyang, and Yibin Kang. “Probing the Fifty Shades of EMT in Metastasis.”. Trends Cancer 22 (2016): , 2, 2, 65-67. Web.Abstract
The involvement of epithelial-to-mesenchymal transition (EMT) in metastasis has long been under debate. Recent efforts to probe the occurrence and functional significance of EMT in clinical samples and animal models have produced exciting but sometimes conflicting findings. The diversity of EMT underlies the challenge in studying its role in metastasis.
Ducker, Gregory S, et al.Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway.”. Cell Metab 23.6 (2016): , 23, 6, 1140-53. Web.Abstract
One-carbon (1C) units for purine and thymidine synthesis can be generated from serine by cytosolic or mitochondrial folate metabolism. The mitochondrial 1C pathway is consistently overexpressed in cancer. Here, we show that most but not all proliferating mammalian cell lines use the mitochondrial pathway as the default for making 1C units. Clustered regularly interspaced short palindromic repeats (CRISPR)-mediated mitochondrial pathway knockout activates cytosolic 1C-unit production. This reversal in cytosolic flux is triggered by depletion of a single metabolite, 10-formyl-tetrahydrofolate (10-formyl-THF), and enables rapid cell growth in nutrient-replete conditions. Loss of the mitochondrial pathway, however, renders cells dependent on extracellular serine to make 1C units and on extracellular glycine to make glutathione. HCT-116 colon cancer xenografts lacking mitochondrial 1C pathway activity generate the 1C units required for growth by cytosolic serine catabolism. Loss of both pathways precludes xenograft formation. Thus, either mitochondrial or cytosolic 1C metabolism can support tumorigenesis, with the mitochondrial pathway required in nutrient-poor conditions.
Liu, Xuesong, et al.Aspiration promotes cooperation in the prisoner's dilemma game with the imitation rule.”. Phys Rev E 94.1-1 (2016): , 94, 1-1, 012124. Web.Abstract
A model of stochastic evolutionary game dynamics with finite population of size N+M was built. Among these individuals, N individuals update strategies with aspiration updating, while the other M individuals update strategies with imitation updating. In the proposed model, we obtain the expression of the mean fraction of cooperators and analyze some concrete cases. Compared with the standard imitation dynamics, there is always a positive probability to support the formation of cooperation in the system with the aspiration and imitation rules. Moreover, the numerical results indicate that more aspiration-driven individuals lead to a higher mean fraction of imitation-driven cooperators, which means the invasion of the aspiration-driven individuals is conducive to promoting the cooperation of the imitation-driven individuals.
Lu, Wei, and Yibin Kang. “Cell lineage determinants as regulators of breast cancer metastasis.”. Cancer Metastasis Rev 35.4 (2016): , 35, 4, 631-644. Web.Abstract
The mammary epithelium is organized in a hierarchy of mammary stem cells (MaSCs), progenitors, and differentiated cells. The development and homeostasis of mammary gland are tightly controlled by a complex network of cell lineage regulators. These determinants of cellular hierarchy are frequently deregulated in breast tumor cells and closely associated with cancer progression and metastasis. They also contribute to the diversity of breast cancer subtypes and their distinct metastatic patterns. Cell fate regulators that normally promote stem/progenitor activities can serve as drivers for epithelial-mesenchymal transition and metastasis whereas regulators that promote terminal differentiation generally suppress metastasis. In this review, we discuss how some of the key factors function in normal mammary lineage determination and how these processes are hijacked by tumor cells to enhance metastasis. Understanding the molecular connections between normal development and cancer metastasis will enable the development of more specific and effective therapeutic approaches targeting metastatic tumor cells.
Peinado, Héctor, et al.Corrigendum: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET.”. Nat Med 22.12 (2016): , 22, 12, 1502. Web.
Ducker, Gregory S, et al.Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway.”. Cell Metab 24.4 (2016): , 24, 4, 640-641. Web.
Liu, Xuesong, et al.Fixation probabilities in evolutionary games with the Moran and Fermi processes.”. J Theor Biol 364 (2015): , 364, 242-8. Web.Abstract
An evolutionary dynamic model of 2×2 games with finite population of size N+M was built. Among these individuals, N individuals have the same update mechanism as that of the Moran process, while the other M individuals have the same update mechanism as that of the Fermi process. We obtain the balance equations of the fixation probability and analyze some concrete cases. In contrast with the results of neutral evolution, the fixation probability of a single co-operator with the same update mechanism as that of the Fermi process is higher. Besides, more co-operators with the update mechanism of the Fermi process lead to higher fixation probabilities when co-operators׳ quantity is the same.
Alečković, Maša, and Yibin Kang. “Regulation of cancer metastasis by cell-free miRNAs.”. Biochim Biophys Acta 1855.1 (2015): , 1855, 1, 24-42. Web.Abstract
MicroRNAs (miRNAs) are integral molecules in the regulation of numerous physiological cellular processes that have emerged as critical players in cancer initiation and metastatic progression, both by promoting and suppressing metastasis. Recently, cell-free miRNAs shed from cancer cells into circulation have been reported in cancer patients, raising hope for development of novel biomarkers that can be routinely measured in easily accessible samples. In fact, establishing miRNA expression in the circulation likely has advantages over determination in primary tumor tissue, further augmenting the potential applications of miRNA detection in oncological practice. In addition, secretion of miRNAs impacting distant cell signaling or promoting the formation of a niche that sustains a distant tumor microenvironment allows for new treatment approaches to thwart cancer progression.
Alečković, Maša, and Yibin Kang. “Bone marrow stroma-derived miRNAs as regulators, biomarkers and therapeutic targets of bone metastasis.”. Bonekey Rep 4 (2015): , 4, 671. Web.Abstract
MicroRNAs (miRNAs) are short, endogenous RNA molecules that have essential roles in regulating gene expression. They control numerous physiological and cellular processes, including normal bone organogenesis and homeostasis, by enhancing or inhibiting bone marrow cell growth, differentiation, functional activity and crosstalk of the multiple cell types within the bone. Hence, elucidating miRNA targets in bone marrow stromal cells has revealed novel regulations during bone development and maintenance. Moreover, recent studies have detailed the capacity for bone stromal miRNAs to influence bone metastasis from a number of primary carcinomas by interfering with bone homeostasis or by directly influencing metastatic tumor cells. Owing to the current lack of good diagnostic biomarkers of bone metastases, such changes in bone stromal miRNA expression in the presence of metastatic lesions may become useful biomarkers, and may even serve as therapeutic targets. In particular, cell-free and exosomal miRNAs shed from bone stromal cells into circulation may be developed into novel biomarkers that can be routinely measured in easily accessible samples. Taken together, these findings reveal the significant role of bone marrow stroma-derived miRNAs in the regulation of bone homeostasis and bone metastasis.
Ren, Guangwen, Mark Esposito, and Yibin Kang. “Bone metastasis and the metastatic niche.”. J Mol Med (Berl) 93.11 (2015): , 93, 11, 1203-12. Web.Abstract
The bone marrow has been long known to host a unique environment amenable to colonization by metastasizing tumor cells. Yet, the underlying molecular interactions within this specialized microenvironment which give rise to the high incidence of bone metastasis in breast and prostate cancer patients have long remained uncharacterized. With the recent description of the bone metastatic "niche," considerable focus has been placed on understanding how the bone stroma contributes to each step of metastasis. Discoveries within this field have demonstrated that when cancer cells home to the niche in which hematopoietic and mesenchymal stem/progenitor cells normally reside, a bidirectional crosstalk emerges between the tumor cells and the bone metastatic stroma. This communication modulates every step of cancer cell metastasis to the bone, including the initial homing and seeding, formation of micrometastases, outgrowth of macrometastases, and the maintenance of long-term dormancy of disseminated tumor cells in the bone. In clinical practice, targeting the bone metastatic niche is evolving into a promising avenue for the prevention of bone metastatic relapse, therapeutic resistance, and other aspects of cancer progression. Here, we review the current knowledge concerning the role of the bone metastatic niche in bone metastasis.
Zheng, Hanqiu, and Yibin Kang. “Cradle of evil: osteogenic niche for early bone metastasis.”. Cancer Cell 27.2 (2015): , 27, 2, 153-5. Web.Abstract
Bone metastasis often emerges long after the initial dissemination of cancer cells. In this issue of Cancer Cell, Wang and colleagues demonstrate that disseminated breast cancer cells engage osteogenic niches in the bone through heterotypic adherins junctions. This interaction activates mTOR signaling in cancer cells and supports their expansion to micrometastases.
Liu, Xuesong, et al.Fixation times in evolutionary games with the Moran and Fermi processes.”. J Theor Biol 387 (2015): , 387, 214-20. Web.Abstract
We combined the standard Moran and Fermi process into a mixed process with two strategies C (co-operation) and D (defection). In a well-mixed population of size N+M, N individuals have the same update mechanism as that of Moran process, while the other M individuals have the same update mechanism as that of Fermi process. We obtain the balance equations of the conditional fixation time and unconditional fixation time. What these equations are doing is to make numerical sense for all the figures. We find that the expectation values of conditional fixation times of a single co-operator are smaller than the average values of the standard Moran and Fermi process. In addition, the conditional fixation time of a single co-operator with update rule of Moran is larger than that of Fermi when the intensity of selection is sufficiently small. The simulation results show that the unconditional fixation time of a co-operator who obtains more information is smaller. In addition, the larger the difference of individuals׳ payoff, the smaller the unconditional fixation time.
Esposito, Mark, and Yibin Kang. “RAI2: Linking Retinoic Acid Signaling with Metastasis Suppression.”. Cancer Discov 55 (2015): , 5, 5, 466-8. Web.Abstract
Considerable evidence points to the importance of disseminated tumor cells, which are commonly detected in the bone marrow and display features of cellular plasticity, in predicting the clinical outcome of breast cancer. In this issue of Cancer Discovery, Werner and colleagues report on the discovery of retinoic acid-induced 2 (RAI2) as a differentiation factor that suppresses early metastatic spread of estrogen receptor-positive breast cancer.
Chakrabarti, Rumela, and Yibin Kang. “Transplantable mouse tumor models of breast cancer metastasis.”. Methods Mol Biol 1267 (2015): , 1267, 367-80. Web.Abstract
Metastatic spread of cancer cells is the main cause of death of breast cancer patients. A better understanding of the molecular mechanism of cancer metastasis is essential for the development of novel and effective therapies. The biological complexity of the metastasis process requires the combination of multiple experimental systems to model distinct steps of cancer metastasis. Several animal models have been generated to mimic the process of breast cancer metastasis, with unique advantages and drawbacks of each model. In this chapter, we describe transplantable xenograft and allograft methods to introduce human or mouse breast tumor cells into mice in order to generate spontaneous and experimental metastasis.
Hoshino, Ayuko, et al.Tumour exosome integrins determine organotropic metastasis.”. Nature 527.7578 (2015): , 527, 7578, 329-35. Web.Abstract
Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.
Wong, Kenneth Kin Lam, et al.β-Spectrin regulates the hippo signaling pathway and modulates the basal actin network.”. J Biol Chem 290.10 (2015): , 290, 10, 6397-407. Web.Abstract
Emerging evidence suggests functional regulation of the Hippo pathway by the actin cytoskeleton, although the detailed molecular mechanism remains incomplete. In a genetic screen, we identified a requirement for β-Spectrin in the posterior follicle cells for the oocyte repolarization process during Drosophila mid-oogenesis. β-spectrin mutations lead to loss of Hippo signaling activity in the follicle cells. A similar reduction of Hippo signaling activity was observed after β-Spectrin knockdown in mammalian cells. We further demonstrated that β-spectrin mutations disrupt the basal actin network in follicle cells. The abnormal stress fiber-like actin structure on the basal side of follicle cells provides a likely link between the β-spectrin mutations and the loss of the Hippo signaling activity phenotype.
Alečković, Maša, and Yibin Kang. “Welcoming Treat: Astrocyte-Derived Exosomes Induce PTEN Suppression to Foster Brain Metastasis.”. Cancer Cell 28.5 (2015): , 28, 5, 554-6. Web.Abstract
Metastasis to distant organs depends on pathological crosstalk between tumor cells and various tissue-specific stromal components. Zhang and colleagues recently demonstrated that astrocyte-derived exosomal miR-19a reversibly downregulated PTEN expression in cancer cells, thereby increasing their CCL2 secretion and recruitment of myeloid cell to promote brain metastasis.
Wang, Yufeng, et al.DLC1-dependent parathyroid hormone-like hormone inhibition suppresses breast cancer bone metastasis.”. J Clin Invest 124.4 (2014): , 124, 4, 1646-59. Web.Abstract
Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-β signaling; however, little is known about how the TGF-β pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-β responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-β-induced expression of parathyroid hormone-like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho-TGF-β crosstalk in osteolytic bone metastasis.
Deng, Yujie, et al.MiR-215 modulates gastric cancer cell proliferation by targeting RB1.”. Cancer Lett 342.1 (2014): , 342, 1, 27-35. Web.Abstract
Growing evidence indicates that miRNAs play critical roles in tumorigenesis and cancer progression. Here, we report that miR-215 is significantly up-regulated in gastric cancer tissues from either gastrectomy or gastroscopy. Receiver Operator Characteristic (ROC) curve analysis indicated that miR-215 may be a candidate biomarker for gastric cancer diagnosis. Inhibition of miR-215 significantly suppressed gastric cancer cell proliferation possibly via G1 arrest. Further analyses indicated that miR-215 was able to target retinoblastoma tumor-suppressor gene 1 (RB1) through its 3'-UTR in gastric cancer cells. These data suggest that frequently up-regulated miR-215 in gastric cancer may influence cell proliferation by targeting RB1.
Li, Wenyang, and Yibin Kang. “A new Lnc in metastasis: long noncoding RNA mediates the prometastatic functions of TGF-β.”. Cancer Cell 25.5 (2014): , 25, 5, 557-9. Web.Abstract
TGF-β signaling promotes metastasis by controlling the expression of downstream target genes. In this issue of Cancer Cell, Yuan and colleagues discover a novel TGF-β-induced lncRNA, lncRNA-ATB, which stimulates EMT through sequestering miR-200s and facilitates colonization by stabilizing IL-11 mRNA, thus promoting both early and late steps of cancer metastasis.
Esposito, Mark, and Yibin Kang. “Targeting tumor-stromal interactions in bone metastasis.”. Pharmacol Ther 141.2 (2014): , 141, 2, 222-33. Web.Abstract
Bone metastasis is a frequent occurrence in late stage solid tumors, including breast cancers, prostate or lung. However, the causes for this proclivity have only recently been elucidated. Significant progress has been made in the past decade toward understanding the molecular underpinnings of bone metastasis, and much of this research reveals a crucial role of the host stroma in each step of the metastatic cascade. Tumor-stromal interactions are crucial in engineering a pre-metastatic niche, accommodating metastatic seeding, and establishing the vicious cycle of bone metastasis. Current treatments in bone metastasis focus on latter steps of the metastatic cascade, with most treatments targeting the process of bone remodeling; however, emerging research identifies many other candidates as promising targets. Host stromal cells including platelets and endothelial cells are important in the early steps of metastatic homing, attachment and extravasation while a variety of immune cells, parenchymal cells and mesenchymal cells of the bone marrow are important in the establishment of overt, immune-suppressed metastatic lesions. Many participants during these steps have been identified and functionally validated. Significant contributors include integrins, (αvβ3, α2β1, α4β1), TGFβ family members, bone resident proteins (BSP, OPG, SPARC, OPN), RANKL, and PTHrP. In this review, we will discuss the contribution of host stromal cells to pre-metastatic niche conditioning, seeding, dormancy, bone-remodeling, immune regulation, and chemotherapeutic shielding in bone metastasis. Research exploring these interactions between bone metastases and stromal cells has yielded many therapeutic targets, and we will discuss both the current and future therapeutic avenues in treating bone metastasis.
Fan, Jun, et al.Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex.”. Mol Cell 53.4 (2014): , 53, 4, 534-48. Web.Abstract
Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homeostasis in mammalian cells. The current understanding of PDC regulation involves inhibitory serine phosphorylation of pyruvate dehydrogenase (PDH) by PDH kinase (PDK), whereas dephosphorylation of PDH by PDH phosphatase (PDP) activates PDC. Here, we report that lysine acetylation of PDHA1 and PDP1 is common in epidermal growth factor (EGF)-stimulated cells and diverse human cancer cells. K321 acetylation inhibits PDHA1 by recruiting PDK1, and K202 acetylation inhibits PDP1 by dissociating its substrate PDHA1, both of which are important in promoting glycolysis in cancer cells and consequent tumor growth. Moreover, we identified mitochondrial ACAT1 and SIRT3 as the upstream acetyltransferase and deacetylase, respectively, of PDHA1 and PDP1, while knockdown of ACAT1 attenuates tumor growth. Furthermore, Y381 phosphorylation of PDP1 dissociates SIRT3 and recruits ACAT1 to PDC. Together, hierarchical, distinct posttranslational modifications act in concert to control molecular composition of PDC and contribute to the Warburg effect.
Cicchini, Michelle, et al.Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity.”. Autophagy 10.11 (2014): , 10, 11, 2036-52. Web.Abstract
Earlier studies reported allelic deletion of the essential autophagy regulator BECN1 in breast cancers implicating BECN1 loss, and likely defective autophagy, in tumorigenesis. Recent studies have questioned the tumor suppressive role of autophagy, as autophagy-related gene (Atg) defects generally suppress tumorigenesis in well-characterized mouse tumor models. We now report that, while it delays or does not alter mammary tumorigenesis driven by Palb2 loss or ERBB2 and PyMT overexpression, monoallelic Becn1 loss promotes mammary tumor development in 2 specific contexts, namely following parity and in association with wingless-type MMTV integration site family, member 1 (WNT1) activation. Our studies demonstrate that Becn1 heterozygosity, which results in immature mammary epithelial cell expansion and aberrant TNFRSF11A/TNR11/RANK (tumor necrosis factor receptor superfamily, member 11a, NFKB activator) signaling, promotes mammary tumorigenesis in multiparous FVB/N mice and in cooperation with the progenitor cell-transforming WNT1 oncogene. Similar to our Becn1(+/-);MMTV-Wnt1 mouse model, low BECN1 expression and an activated WNT pathway gene signature correlate with the triple-negative subtype, TNFRSF11A axis activation and poor prognosis in human breast cancers. Our results suggest that BECN1 may have nonautophagy-related roles in mammary development, provide insight in the seemingly paradoxical roles of BECN1 in tumorigenesis, and constitute the basis for further studies on the pathophysiology and treatment of clinically aggressive triple negative breast cancers (TNBCs).
Wan, Liling, et al.Genetic ablation of metadherin inhibits autochthonous prostate cancer progression and metastasis.”. Cancer Res 74.18 (2014): , 74, 18, 5336-47. Web.Abstract
Metadherin (MTDH) overexpression in diverse cancer types has been linked to poor clinical outcomes, but definitive genetic proof of its contributions to cancer remains incomplete. In particular, the degree to which MTDH may contribute to malignant progression in vivo is lacking. Here, we report that MTDH is amplified frequently in human prostate cancers where its expression levels are tightly correlated with prostate cancer progression and poor disease-free survival. Furthermore, we show that genetic ablation of MTDH in the transgenic adenomcarcinoma of mouse prostate (TRAMP) transgenic mouse model of prostate cancer blocks malignant progression without causing defects in the normal development of the prostate. Germline deletion of Mtdh in TRAMP mice prolonged tumor latency, reduced tumor burden, arrested progression of prostate cancer at well-differentiated stages, and inhibited systemic metastasis to distant organs, thereby decreasing cancer-related mortality ∼10-fold. Consistent with these findings, direct silencing of Mtdh in prostate cancer cells decreased proliferation in vitro and tumor growth in vivo, supporting an epithelial cell-intrinsic role of MTDH in prostate cancer. Together, our findings establish a pivotal role for MTDH in prostate cancer progression and metastasis and define MTDH as a therapeutic target in this setting. Cancer Res; 74(18); 5336-47. ©2014 AACR.
Ell, Brian, et al.The microRNA-23b/27b/24 cluster promotes breast cancer lung metastasis by targeting metastasis-suppressive gene prosaposin.”. J Biol Chem 289.32 (2014): , 289, 32, 21888-95. Web.Abstract
MicroRNAs (miRNAs) have been shown to function as key regulators of tumor progression and metastasis. Recent studies have indicated that the miRNAs comprising the miR-23b/27b/24 cluster might influence tumor metastasis, although the precise nature of this regulation remains unclear. Here, expression of the miR-23b/27b/24 cluster is found to correlate with metastatic potential in mouse and human breast cancer cell lines and is elevated in metastatic lung lesions in human breast cancer patients. Ectopic expression of the miRNAs in the weakly metastatic mouse 4TO7 mammary tumor cell line had no effect on proliferation or morphology of tumor cells in vitro but was found to increase lung metastasis in a mouse model of breast cancer metastasis. Furthermore, gene expression profiling analysis of miRNA overexpressing 4TO7 cells revealed the direct targeting of prosaposin (PSAP), which encodes a secreted protein found to be inversely correlated with metastatic progression in human breast cancer patients. Importantly, ectopic expression of PSAP was able to suppress the metastatic phenotype in highly metastatic 4T1 and MDA-MB-231 SCP28 cells, as well as in cells ectopically expressing miR-23b/27b/24. These findings support a metastasis-promoting function of the miR-23b/27b/24 cluster of miRNAs, which functions in part through the direct inhibition of PSAP.
Ell, Brian, and Yibin Kang. “MicroRNAs as regulators of bone homeostasis and bone metastasis.”. Bonekey Rep 3 (2014): , 3, 549. Web.Abstract
MicroRNAs (miRNAs) are short, endogenous RNAs that have essential roles in regulating gene expression through the disruption of target genes. The miRNA-induced suppression can occur through Argonaute-mediated cleavage of target mRNAs or by translational inhibition. System-wide studies have underscored the integral role that miRNAs play in regulating the expression of essential genes within bone marrow stromal cells. The miRNA expression has been shown to enhance or inhibit cell differentiation and activity, and elucidating miRNA targets within bone marrow cells has revealed novel regulations during normal bone development. Importantly, multiple studies have shown that miRNA misexpression mediates the progression of bone-related pathologies, including osteopetrosis and osteoporosis, as well as the development and progression of osteosarcoma. Furthermore, recent studies have detailed the capacity for miRNAs to influence bone metastasis from a number of primary carcinomas. Taken together, these findings reveal the significant clinical potential for miRNAs to regulate bone homeostasis, as well as to mediate bone-related pathologies.
Wan, Liling, et al.MTDH-SND1 interaction is crucial for expansion and activity of tumor-initiating cells in diverse oncogene- and carcinogen-induced mammary tumors.”. Cancer Cell 26.1 (2014): , 26, 1, 92-105. Web.Abstract
The Metadherin gene (MTDH) is prevalently amplified in breast cancer and associated with poor prognosis; however, its functional contribution to tumorigenesis is poorly understood. Using mouse models representing different subtypes of breast cancer, we demonstrated that MTDH plays a critical role in mammary tumorigenesis by regulating oncogene-induced expansion and activities of tumor-initiating cells (TICs), whereas it is largely dispensable for normal development. Mechanistically, MTDH supports the survival of mammary epithelial cells under oncogenic/stress conditions by interacting with and stabilizing Staphylococcal nuclease domain-containing 1 (SND1). Silencing MTDH or SND1 individually or disrupting their interaction compromises tumorigenenic potential of TICs in vivo. This functional significance of MTDH-SND1 interaction is further supported by clinical analysis of human breast cancer samples.
Zheng, Hanqiu, et al.PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis.”. Cancer Cell 26.3 (2014): , 26, 3, 358-73. Web.Abstract
Metastatic dissemination is often initiated by the reactivation of an embryonic development program referred to as epithelial-mesenchymal transition (EMT). The transcription factor SNAIL promotes EMT and elicits associated pathological characteristics such as invasion, metastasis, and stemness. To better understand the posttranslational regulation of SNAIL, we performed a luciferase-based, genome-wide E3 ligase siRNA library screen and identified SCF-FBXO11 as an important E3 that targets SNAIL for ubiquitylation and degradation. Furthermore, we discovered that SNAIL degradation by FBXO11 is dependent on Ser-11 phosphorylation of SNAIL by protein kinase D1 (PKD1). FBXO11 blocks SNAIL-induced EMT, tumor initiation, and metastasis in multiple breast cancer models. These findings establish the PKD1-FBXO11-SNAIL axis as a mechanism of posttranslational regulation of EMT and cancer metastasis.
Guo, Feng, et al.Structural insights into the tumor-promoting function of the MTDH-SND1 complex.”. Cell Rep 86 (2014): , 8, 6, 1704-13. Web.Abstract
Metadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1) are overexpressed and interact in diverse cancer types. The structural mechanism of their interaction remains unclear. Here, we determined the high-resolution crystal structure of MTDH-SND1 complex, which reveals an 11-residue MTDH peptide motif occupying an extended protein groove between two SN domains (SN1/2), with two MTDH tryptophan residues nestled into two well-defined pockets in SND1. At the opposite side of the MTDH-SND1 binding interface, SND1 possesses long protruding arms and deep surface valleys that are prone to binding with other partners. Despite the simple binding mode, interactions at both tryptophan-binding pockets are important for MTDH and SND1's roles in breast cancer and for SND1 stability under stress. Our study reveals a unique mode of interaction with SN domains that dictates cancer-promoting activity and provides a structural basis for mechanistic understanding of MTDH-SND1-mediated signaling and for exploring therapeutic targeting of this complex.
Chakrabarti, Rumela, et al.ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signalling.”. Nat Cell Biol 16.10 (2014): , 16, 10, 1004-15, 1-13. Web.Abstract
Emerging evidence suggests that cancer is populated and maintained by tumour-initiating cells (TICs) with stem-like properties similar to those of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the ΔNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7, thereby enhancing Wnt signalling. Importantly, Fzd7-dependent enhancement of Wnt signalling by ΔNp63 also governs tumour-initiating activity of the basal subtype of breast cancer. These findings establish ΔNp63 as a key regulator of stem cells in both normal and malignant mammary tissues and provide direct evidence that breast cancer TICs and normal MaSCs share common regulatory mechanisms.