PLX266583

GSE125109: TGFR and Hh signalling regulate prognostic matrisome molecules in ovarian cancer

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

We previously identified a matrisome gene expression signature with prognostic significance in high-grade serous ovarian cancer (HGSOC) and twelve other human solid cancers. Here, our aim was to understand regulation of six matrisome molecules of this prognostic signature, COL11A1, COMP, FN1, VCAN, CTSB and COL1A1, that were significantly upregulated with disease progression. We used HGSOC biopsies and transcriptional databases to identify the cells and signalling pathways involved, validating these in monocultures and novel 3D tri-cultures. Using in silico analyses, we identified TGF and Hh signalling as key regulators. Monocultures confirmed matrisome molecule production by activated omental fibroblasts, directed by TGFR and Hh signalling crosstalk. Malignant cell production of the six molecules was less and variable. We built novel 3D tri-cultures of HGSOC cells with human primary omental adipocytes and fibroblasts. The tri-cultures replicated tissue remodelling and matrisome production observed in biopsies. RNAseq analysis showed that tri-cultures reproduced the prognostic matrisome signature. TGFR and Hh inhibitors attenuated fibroblast activation, gel remodelling and matrisome production in tri-cultures. We conclude that fibroblast activation and matrisome deposition occurs following activation of the Hh pathway by TGF secreted from malignant cells and that our tri-culture model can replicate important features of the tumor microenvironment.; We report RNA sequencing results of novel 3D COL1-gel tri-cultures of high-grade serous ovarian cancer (HGSOC) malignant cells with human primary omental adipocytes and fibroblasts in the presence or absence of TGFR and Hh inhibitors combination. We also provide the transcriptional profiles of three HGSOC malignant cell lines grown in monolayer and as spheroids. SOURCE: Eleni Maniati (e.maniati@qmul.ac.uk) - Cancer and Inflammation Queen Mary University of London