Project description:Cancer-associated fibroblasts promote the development of many primary malignancies, but their function in metastatic progression is poorly understood. Here, we demonstrate that colonization of the lungs by metastatic breast cancer cells induces an inflammatory phenotype in lung fibroblasts. CXCL9 and CXCL10 are induced in an NFκB-dependent manner in metastasis-associated fibroblasts in response IL-1α and IL-1β secreted by disseminated breast cancer cells. We find that the chemokine receptor CXCR3, that binds CXCL9/10, is expressed in a small subset of breast cancer cells that exhibits greater tumor-initiating ability when co-transplanted with fibroblasts. CXCR3-expressing cancer cells maintain JNK signaling that drives IL-1A/B expression, and thus rendering this subpopulation efficient in both inducing CXCL9/10 in lung fibroblasts and responding to the chemokines. Importantly, disruption of the CXCL9/10-CXCR3 axis significantly reduces metastatic colonization in xenograft and syngeneic mouse models suggesting an essential role of this paracrine crosstalk in metastatic progression and a potential therapeutic vulnerability for the treatment of metastatic breast cancer.
Project description:RNA-sequencing was performed in SUM 159 parental and PTX resistant breast cancer cells in an effort to identify novel regulators of chemoresistance that could potentially be targeted in Triple Negative Breast Cancer (TNBC). The bioinformatic analysis identified numerous differentially expressed genes including several known chemoresistance markers, as well as novel genes that may play an important role in breast cancer chemoresistant cells.
Project description:In cancer progression to metastasis, disseminated cancer cells frequently lodge near vasculature in secondary organs. However, our understanding of the cellular crosstalk evoked at perivascular sites is still rudimentary. In this study, we identified an inter-cellular machinery governing formation of a pro-metastatic vascular niche during breast cancer colonization in lungs. Transcriptomic analysis of endothelial cells (ECs) isolated from mouse lungs with metastases revealed a marked upregulation of genes linked to proliferation, inflammation and numerous secreted proteins. We showed that four secreted factors, INHBB, SCGB3A1, OPG and LAMA1, induced in ECs form a supportive niche that promotes metastasis in mice, by enhancing stem cell properties and survival ability of cancer cells. Interestingly, the blocking vascular endothelial cell growth factor (VEGF), a major cytokine regulating EC behaviors, dramatically suppressed EC proliferation whereas no impact was observed on the expression of the four vascular niche factors in lung ECs. We found that the formation of a vascular niche is correlated with inflammation, and revealed that metastasis-associated macrophages are essential for production of all of four niche factors in lung ECs. Macrophages are activated via TNC-TLR4 at perivasculature and sequentially stimulate ECs to produce the four niche factors. Thus, our findings provide mechanistic insights into the formation of a perivascular niche and offer the possibility that targeting macrophages may synergize with existing anti-angiogenic drugs to effectively suppress vascular function in metastatic colonization. We used microarrays to analyze the global changes of gene expression in SUM-LM1 human breast cancer cells upon treatment with Activin B
Project description:Overexpression of Pierce1 in the breast cancer cell line SUM-159-PT (SUM) induced a higher resistance to anticancer drugs. To investigate the molecular basis of this chemoresistance, SUM cells overexpressing human Pierce1 (SUM-Pierce1) were compared to control cells (SUM-CTLR).
Project description:RNA-sequencing for the characterization of the transcriptome of SUM 159 parental and Paclitaxel (PTX) resistant breast cancer cells.
Project description:Immune surveillance plays a pivotal role in controlling tumor emergence, dormancy and progression, including in breast cancer. Despite its potential clinical relevance, the mechanisms governing dormancy initiation, maintenance and escape, as well as the molecular mediators involved, remain poorly understood. Here, we identify the interferon-inducible chemokine CXCL10 and its receptor CXCR3 as key regulators of immunological dormancy in triple-negative breast cancer (TNBC). By transcriptomic profiling, we observed high expression of Cxcl10 in dormant cells in two different orthotopic, syngeneic models of breast cancer dormancy (D2.0R and 4T1-MR20). Genetic silencing of Cxcl10 in dormant cells or pharmacological blockade of CXCR3 in vivo led to early tumor onset and rapid growth in immunocompetent mice. In contrast, dormant cells effectively formed tumors in immune-deficient mice independently of Cxcl10 status, demonstrating that the CXCL10/CXCR3 axis-mediated dormancy requires a functional immune system. Further analysis confirmed that Cxcl10 silencing altered the local immune microenvironment, reducing CD4+ and CD8+ T cell infiltration while increasing the presence of granulocytic Myeloid Derived Suppressor Cells and Natural Killer cells. Moreover, Cxcl10 silencing significantly increased the burden of tumor cells disseminated to the lung. Leveraging these findings, we identified a CXCL10-mediated dormancy signature that predicts improved overall survival in TNBC patients. Our findings have identified a new mechanism modulating breast cancer dormancy with two important clinical implications: the CXCL10/CXCR3 axis as a potential therapeutic target for improving survival of patients with TNBC, and the CXCL10-dependent dormancy signature as a tool for identifying these patients.