Netrin signaling mediates survival of dormant epithelial ovarian cancer cells
Netrin signaling mediates survival of dormant epithelial ovarian cancer cells
Abstract 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.
Mehlen Patrick、MacDonald James I.、Wasif Sumaiyah、Gibert Benjamin、Passos Daniel T.、Dick Frederick A.、Ramos-Valdes Yudith、Rottapel Rob、Hervieu Ma?va、Perampalam Pirunthan、Shepherd Trevor G.、Correa Rohann、Zakirova Komila
Apoptosis, Cancer and Development Laboratory - Equipe labellis¨|e ??La Ligue?ˉ, LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Canc¨|rologie de Lyon (CRCL) Universit¨| de Lyon, Universit¨| Claude Bernard Lyon1, Centre L¨|on B¨|rard||Netris PharmaLondon Regional Cancer Program, London Health Sciences Centre Research Institute||Department of Pathology and Laboratory Medicine, University of Western OntarioLondon Regional Cancer Program, London Health Sciences Centre Research Institute||Department of Pathology and Laboratory Medicine, University of Western OntarioApoptosis, Cancer and Development Laboratory - Equipe labellis¨|e ??La Ligue?ˉ, LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Canc¨|rologie de Lyon (CRCL) Universit¨| de Lyon, Universit¨| Claude Bernard Lyon1, Centre L¨|on B¨|rardLondon Regional Cancer Program, London Health Sciences Centre Research Institute||Department of Pathology and Laboratory Medicine, University of Western OntarioLondon Regional Cancer Program, London Health Sciences Centre Research Institute||Department of Pathology and Laboratory Medicine, University of Western Ontario||Department of Oncology, Western University||Children?ˉs Health Research InstituteLondon Regional Cancer Program, London Health Sciences Centre Research Institute||The Mary and John Knight Translational Ovarian Cancer Research UnitPrincess Margaret Cancer Centre, University Health Network, 101 College Street||Department of Medical Biophysics, University of Toronto, 1 King?ˉs College CircleApoptosis, Cancer and Development Laboratory - Equipe labellis¨|e ??La Ligue?ˉ, LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Canc¨|rologie de Lyon (CRCL) Universit¨| de Lyon, Universit¨| Claude Bernard Lyon1, Centre L¨|on B¨|rardLondon Regional Cancer Program, London Health Sciences Centre Research Institute||Department of Biochemistry, University of Western OntarioLondon Regional Cancer Program, London Health Sciences Centre Research Institute||The Mary and John Knight Translational Ovarian Cancer Research Unit||Department of Oncology, Western University||Department of Obstetrics and Gynecology, Western University||Department of Anatomy and Cell Biology, Western UniversityLondon Regional Cancer Program, London Health Sciences Centre Research Institute||Department of Oncology, Western UniversityLondon Regional Cancer Program, London Health Sciences Centre Research Institute||Department of Pathology and Laboratory Medicine, University of Western Ontario
肿瘤学医学研究方法基础医学
Netrinhigh grade serous ovarian cancerDYRK1Adormancyquiescencespheroids
Mehlen Patrick,MacDonald James I.,Wasif Sumaiyah,Gibert Benjamin,Passos Daniel T.,Dick Frederick A.,Ramos-Valdes Yudith,Rottapel Rob,Hervieu Ma?va,Perampalam Pirunthan,Shepherd Trevor G.,Correa Rohann,Zakirova Komila.Netrin signaling mediates survival of dormant epithelial ovarian cancer cells[EB/OL].(2025-03-28)[2025-05-16].https://www.biorxiv.org/content/10.1101/2023.08.29.555435.点此复制
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