Ovarian Carcinoma-Associated Mesenchymal Stem Cells Arise from Tissue-Specific Normal Stroma
AuthorCoffman, LG; Pearson, AT; Frisbie, LG; Freeman, Z; Christie, E; Bowtell, DD; Buckanovich, RJ
Source TitleStem Cells
AffiliationSir Peter MacCallum Department of Oncology
Document TypeJournal Article
CitationsCoffman, L. G., Pearson, A. T., Frisbie, L. G., Freeman, Z., Christie, E., Bowtell, D. D. & Buckanovich, R. J. (2019). Ovarian Carcinoma-Associated Mesenchymal Stem Cells Arise from Tissue-Specific Normal Stroma. STEM CELLS, 37 (2), pp.257-269. https://doi.org/10.1002/stem.2932.
Access StatusOpen Access
Carcinoma-associated mesenchymal stem cells (CA-MSCs) are critical stromal progenitor cells within the tumor microenvironment (TME). We previously demonstrated that CA-MSCs differentially express bone morphogenetic protein family members, promote tumor cell growth, increase cancer "stemness," and chemotherapy resistance. Here, we use RNA sequencing of normal omental MSCs and ovarian CA-MSCs to demonstrate global changes in CA-MSC gene expression. Using these expression profiles, we create a unique predictive algorithm to classify CA-MSCs. Our classifier accurately distinguishes normal omental, ovary, and bone marrow MSCs from ovarian cancer CA-MSCs. Suggesting broad applicability, the model correctly classifies pancreatic and endometrial cancer CA-MSCs and distinguishes cancer associated fibroblasts from CA-MSCs. Using this classifier, we definitively demonstrate ovarian CA-MSCs arise from tumor mediated reprograming of local tissue MSCs. Although cancer cells alone cannot induce a CA-MSC phenotype, the in vivo ovarian TME can reprogram omental or ovary MSCs to protumorigenic CA-MSCs (classifier score of >0.96). In vitro studies suggest that both tumor secreted factors and hypoxia are critical to induce the CA-MSC phenotype. Interestingly, although the breast cancer TME can reprogram bone marrow MSCs into CA-MSCs, the ovarian TME cannot, demonstrating for the first time that tumor mediated CA-MSC conversion is tissue and cancer type dependent. Together these findings (a) provide a critical tool to define CA-MSCs and (b) highlight cancer cell influence on distinct normal tissues providing powerful insights into the mechanisms underlying cancer specific metastatic niche formation. Stem Cells 2019;37:257-269.
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