Modelling TGFβR and Hh pathway regulation of prognostic matrisome molecules in ovarian cancer

In a multi-level “deconstruction” of omental metastases, we previously identified a prognostic matrisome gene expression signature in high-grade serous ovarian cancer (HGSOC) and twelve other malignancies. Here, our aim was to understand how six of these extracellular matrix (ECM) molecules, COL11A1, cartilage oligomeric matrix protein, FN1, versican, cathepsin B, and COL1A1, are upregulated in cancer. Using biopsies, we identified significant associations between TGFβR activity, Hedgehog (Hh) signaling, and these ECM molecules and studied the associations in mono-, co-, and tri-culture. Activated omental fibroblasts (OFs) produced more matrix than malignant cells, directed by TGFβR and Hh signaling cross talk. We “reconstructed” omental metastases in tri-cultures of HGSOC cells, OFs, and adipocytes. This combination was sufficient to generate all six ECM proteins and the matrisome expression signature. TGFβR and Hh inhibitor combinations attenuated fibroblast activation and gel and ECM remodeling in these models. The tri-culture model reproduces key features of omental metastases and allows study of diseased-associated ECM. [Display omitted] •Increase in six ECM molecules in biopsies associates with poor prognosis in HGSOC•These six ECM molecules are produced in tri-cultures, predominantly by fibroblasts•TGF-β and Hedgehog pathway cross talk involved in ECM production in tri-cultures•Tri-cultures recapitulate aspects of ECM production and regulation in biopsies Molecular biology; Tissue engineering; Cancer