A human multi-cellular model shows how platelets drive production of diseased extracellular matrix and tissue invasion
Beatrice Malacrida,
Sam Nichols,
Eleni Maniati,
Roanne Jones,
Robin Delanie-Smith,
Reza Roozitalab,
Eleanor J. Tyler,
Morgan Thomas,
Gina Boot,
Jonas Mackerodt,
Michelle Lockley,
Martin M. Knight,
Frances R. Balkwill,
Oliver M.T. Pearce
Affiliations
Beatrice Malacrida
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Sam Nichols
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Eleni Maniati
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Roanne Jones
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Robin Delanie-Smith
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; School of Engineering and Materials Science, Queen Mary University of London, Mile End, London E1 4NS, UK
Reza Roozitalab
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Eleanor J. Tyler
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Morgan Thomas
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Gina Boot
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Jonas Mackerodt
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Michelle Lockley
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Martin M. Knight
School of Engineering and Materials Science, Queen Mary University of London, Mile End, London E1 4NS, UK
Frances R. Balkwill
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Oliver M.T. Pearce
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Corresponding author
Summary: Guided by a multi-level “deconstruction” of omental metastases, we developed a tetra (four cell)-culture model of primary human mesothelial cells, fibroblasts, adipocytes, and high-grade serous ovarian cancer (HGSOC) cell lines. This multi-cellular model replicated key elements of human metastases and allowed malignant cell invasion into the artificial omental structure. Prompted by findings in patient biopsies, we used the model to investigate the role of platelets in malignant cell invasion and extracellular matrix, ECM, production. RNA (sequencing and quantitative polymerase-chain reaction), protein (proteomics and immunohistochemistry) and image analysis revealed that platelets stimulated malignant cell invasion and production of ECM molecules associated with poor prognosis. Moreover, we found that platelet activation of mesothelial cells was critical in stimulating malignant cell invasion. Whilst platelets likely activate both malignant cells and mesothelial cells, the tetra-culture model allowed us to dissect the role of both cell types and model the early stages of HGSOC metastases.
