Targeting the MAtrix REgulating MOtif, MAREMO, abolishes hallmarks of cancer
Ontology highlight
ABSTRACT:
INSTRUMENT(S): NextSeq 2000
ORGANISM(S): Mus musculus
SUBMITTER: Raphael Carapito
PROVIDER: E-MTAB-13677 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:In the tumor microenvironment the extracellular matrix molecule tenascin-C is highly expressed which correlates with worsened survival prognosis. Tenascin-C promotes multiple steps in cancer progression. In particular, tenascin-C promotes the tumor angiogenic switch and the formation of more but poorly functional blood vessels by ill defined mechanisms. Here, we studied tenascin-C angio-modulatory functions by tumor and stromal cells. Unexpectedly, we observed that direct contact of endothelial cells with tenascin-C impairs angiogenesis through disruption of actin polymerization. This resulted in cytoplasmic retention of the F-actin sensor and co-transcription factor YAP and led to downregulation of YAP pro-angiogenic target genes. Conversely, tumor cells and carcinoma associated fibroblasts exposed to tenascin-C secreted pro-angiogenic factors that promoted endothelial cell survival and tubulogenesis. We identified and functionally validated CXCL12 and Ephrin- B2 as important pro-angiogenic effectors of tenascin-C. Proteomic analysis of the secretome of tumor cells exposed to tenascin-C revealed a signature that predicts shorter survival of patients with low grade glioma and glioblastoma with a particular significance for a combined expression of tenascin-C and Ephrin-B2. Altogether, we demonstrated a dual mechanism of action of tenascin-C in tumor angiogenesis where direct contact of endothelial cells with tenascin-C impairs angiogenesis, and paracrine signals derived from contact of tumor cells and carcinoma associated fibroblasts with tenascin-C promotes angiogenesis. These opposing effects provide for the first time an explanation of divergent mechanisms controlled by tenascin-C which can result in a denser but less functional tumor blood vasculature and might unveil new targeting and prediction opportunities.
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