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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, \u20133, 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 \u20133 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.<\/jats:p>","DOI":"10.7554\/elife.91766","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T11:45:09Z","timestamp":1701344709000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.91766","source":"Crossref","is-referenced-by-count":3,"title":["Netrin signaling mediates survival of dormant epithelial ovarian cancer cells"],"prefix":"10.7554","volume":"12","author":[{"given":"Pirunthan","family":"Perampalam","sequence":"first","affiliation":[{"name":"London Regional Cancer Program, London Health Sciences Centre Research Institute","place":["London, Canada"]},{"id":[{"id":"https:\/\/ror.org\/02grkyz14","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry, University of Western Ontario","place":["London, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"James I","family":"MacDonald","sequence":"additional","affiliation":[{"name":"London Regional Cancer Program, London Health Sciences Centre Research Institute","place":["London, Canada"]},{"id":[{"id":"https:\/\/ror.org\/02grkyz14","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology and Laboratory Medicine, University of Western Ontario","place":["London, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Komila","family":"Zakirova","sequence":"additional","affiliation":[{"name":"London Regional Cancer Program, London Health Sciences Centre Research Institute","place":["London, Canada"]},{"id":[{"id":"https:\/\/ror.org\/02grkyz14","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology and Laboratory Medicine, University of Western Ontario","place":["London, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3530-2821","authenticated-orcid":true,"given":"Daniel T","family":"Passos","sequence":"additional","affiliation":[{"name":"London Regional Cancer Program, London Health Sciences Centre Research Institute","place":["London, Canada"]},{"id":[{"id":"https:\/\/ror.org\/02grkyz14","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology and Laboratory Medicine, University of Western Ontario","place":["London, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Sumaiyah","family":"Wasif","sequence":"additional","affiliation":[{"name":"London Regional Cancer Program, London Health Sciences Centre Research Institute","place":["London, Canada"]},{"id":[{"id":"https:\/\/ror.org\/02grkyz14","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology and Laboratory Medicine, University of Western Ontario","place":["London, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Yudith","family":"Ramos-Valdes","sequence":"additional","affiliation":[{"name":"London Regional Cancer Program, London Health Sciences Centre Research Institute","place":["London, Canada"]},{"name":"The Mary and John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program","place":["London, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Maeva","family":"Hervieu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cmnjq37","id-type":"ROR","asserted-by":"publisher"}],"name":"Apoptosis, Cancer and Development Laboratory - 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