Mouse Ovarian Cancer Models Recapitulate the Human Tumor Microenvironment and Patient Response to Treatment
Eleni Maniati,
Chiara Berlato,
Ganga Gopinathan,
Owen Heath,
Panoraia Kotantaki,
Anissa Lakhani,
Jacqueline McDermott,
Colin Pegrum,
Robin M. Delaine-Smith,
Oliver M.T. Pearce,
Priyanka Hirani,
Joash D. Joy,
Ludmila Szabova,
Ruth Perets,
Owen J. Sansom,
Ronny Drapkin,
Peter Bailey,
Frances R. Balkwill
Affiliations
Eleni Maniati
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Chiara Berlato
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Ganga Gopinathan
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Owen Heath
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Panoraia Kotantaki
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Anissa Lakhani
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Jacqueline McDermott
University College Hospital, UCLH Cellular Pathology, 11-20 Capper Street, London WC1E 6JA, UK
Colin Pegrum
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Robin M. Delaine-Smith
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Oliver M.T. Pearce
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Priyanka Hirani
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Joash D. Joy
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
Ludmila Szabova
Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research at the National Cancer Institute-Frederick, Frederick, MD, USA
Ruth Perets
Rambam Health Care Campus, Technion - Israel Institute of Technology, Haifa, Israel
Owen J. Sansom
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1QH, UK
Ronny Drapkin
Penn Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Peter Bailey
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK; Department for Surgical Research, Universitätsklinikum Erlangen, Erlangen, Germany
Frances R. Balkwill
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK; Corresponding author
Summary: Although there are many prospective targets in the tumor microenvironment (TME) of high-grade serous ovarian cancer (HGSOC), pre-clinical testing is challenging, especially as there is limited information on the murine TME. Here, we characterize the TME of six orthotopic, transplantable syngeneic murine HGSOC lines established from genetic models and compare these to patient biopsies. We identify significant correlations between the transcriptome, host cell infiltrates, matrisome, vasculature, and tissue modulus of mouse and human TMEs, with several stromal and malignant targets in common. However, each model shows distinct differences and potential vulnerabilities that enabled us to test predictions about response to chemotherapy and an anti-IL-6 antibody. Using machine learning, the transcriptional profiles of the mouse tumors that differed in chemotherapy response are able to classify chemotherapy-sensitive and -refractory patient tumors. These models provide useful pre-clinical tools and may help identify subgroups of HGSOC patients who are most likely to respond to specific therapies. : Maniati et al. show how orthotopic transplantable mouse ovarian cancers with appropriate genotypes develop microenvironments that replicate many features of human primary ovarian tumors and metastases. Molecular features of the mouse tumors combined with machine learning may allow the identification of patients who are most likely to respond to specific therapies. Keywords: ovarian cancer, tumor microenvironment, matrisome, serous, mouse model
