Modelling TGFβR and Hh pathway regulation of prognostic matrisome molecules in ovarian cancer
Robin M. Delaine-Smith,
Eleni Maniati,
Beatrice Malacrida,
Sam Nichols,
Reza Roozitalab,
Roanne R. Jones,
Laura S.M. Lecker,
Oliver M.T. Pearce,
Martin M. Knight,
Frances R. Balkwill
Affiliations
Robin M. Delaine-Smith
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square EC1M 6BQ, London, UK; Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, Mile End Road E1, London, UK
Eleni Maniati
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square EC1M 6BQ, London, UK
Beatrice Malacrida
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square EC1M 6BQ, London, UK
Sam Nichols
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square EC1M 6BQ, London, UK
Reza Roozitalab
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square EC1M 6BQ, London, UK
Roanne R. Jones
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square EC1M 6BQ, London, UK
Laura S.M. Lecker
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square EC1M 6BQ, London, UK
Oliver M.T. Pearce
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square EC1M 6BQ, London, UK
Martin M. Knight
Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, Mile End Road E1, London, UK
Frances R. Balkwill
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square EC1M 6BQ, London, UK; Corresponding author
Summary: 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.
