Netrin signaling mediates survival of dormant epithelial ovarian cancer cells
Pirunthan Perampalam,
James I MacDonald,
Komila Zakirova,
Daniel T Passos,
Sumaiyah Wasif,
Yudith Ramos-Valdes,
Maeva Hervieu,
Patrick Mehlen,
Rob Rottapel,
Benjamin Gibert,
Rohann JM Correa,
Trevor G Shepherd,
Frederick A Dick
Affiliations
Pirunthan Perampalam
London Regional Cancer Program, London Health Sciences Centre Research Institute, London, Canada; Department of Biochemistry, University of Western Ontario, London, Canada
James I MacDonald
London Regional Cancer Program, London Health Sciences Centre Research Institute, London, Canada; Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Canada
Komila Zakirova
London Regional Cancer Program, London Health Sciences Centre Research Institute, London, Canada; Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Canada
London Regional Cancer Program, London Health Sciences Centre Research Institute, London, Canada; Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Canada
Sumaiyah Wasif
London Regional Cancer Program, London Health Sciences Centre Research Institute, London, Canada; Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Canada
Yudith Ramos-Valdes
London Regional Cancer Program, London Health Sciences Centre Research Institute, London, Canada; The Mary and John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, Canada
Maeva Hervieu
Apoptosis, Cancer and Development Laboratory - Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, Lyon, France
Patrick Mehlen
Apoptosis, Cancer and Development Laboratory - Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, Lyon, France; Netris Pharma, Lyon, France
Rob Rottapel
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Biophysics, University of Toronto, 1 King’s College Circle, Toronto, Canada
Apoptosis, Cancer and Development Laboratory - Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, Lyon, France
Rohann JM Correa
London Regional Cancer Program, London Health Sciences Centre Research Institute, London, Canada; Department of Oncology, Western University, London, Canada
Trevor G Shepherd
London Regional Cancer Program, London Health Sciences Centre Research Institute, London, Canada; The Mary and John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, Canada; Department of Oncology, Western University, London, Canada; Department of Obstetrics and Gynecology, Western University, London, Canada; Department of Anatomy and Cell Biology, Western University, London, Canada
London Regional Cancer Program, London Health Sciences Centre Research Institute, London, Canada; Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Canada; Department of Oncology, Western University, London, Canada; Children's Health Research Institute, London, Canada
Dormancy in cancer is a clinical state in which residual disease remains undetectable for a prolonged duration. At a cellular level, rare cancer cells cease proliferation and survive chemotherapy and disseminate disease. We created a suspension culture model of high-grade serous ovarian cancer (HGSOC) dormancy and devised a novel CRISPR screening approach to identify survival genes in this context. In combination with RNA-seq, we discovered the Netrin signaling pathway as critical to dormant HGSOC cell survival. We demonstrate that Netrin-1, –3, and its receptors are essential for low level ERK activation to promote survival, and that Netrin activation of ERK is unable to induce proliferation. Deletion of all UNC5 family receptors blocks Netrin signaling in HGSOC cells and compromises viability during the dormancy step of dissemination in xenograft assays. Furthermore, we demonstrate that Netrin-1 and –3 overexpression in HGSOC correlates with poor outcome. Specifically, our experiments reveal that Netrin overexpression elevates cell survival in dormant culture conditions and contributes to greater spread of disease in a xenograft model of abdominal dissemination. This study highlights Netrin signaling as a key mediator HGSOC cancer cell dormancy and metastasis.
