Netrin-1 and UNC5B Cooperate with Integrins to Mediate YAP-Driven Cytostasis.

Autor:	Pearson JD; Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, Canada.; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.; Paul Albrechtsen Research Institute CancerCare Manitoba & Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada., Huang K; Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, Canada., Dela Pena LG; Paul Albrechtsen Research Institute CancerCare Manitoba & Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada., Ducarouge B; Netris Pharma, Centre Léon Bérard 28 Rue Laennec, Lyon, France., Mehlen P; Netris Pharma, Centre Léon Bérard 28 Rue Laennec, Lyon, France.; Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue', LabEX DEVweCAN, Centre de Recherche en Cancérologie de Lyon, Lyon, France., Bremner R; Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, Canada.; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 Sep 01; Vol. 4 (9), pp. 2374-2383.
DOI:	10.1158/2767-9764.CRC-24-0101
Abstrakt:	Opposite expression and pro- or anti-cancer function of YAP and its paralog TAZ/WWTR1 stratify cancers into binary YAPon and YAPoff classes. These transcriptional coactivators are oncogenic in YAPon cancers. In contrast, YAP/TAZ are silenced epigenetically along with their integrin and extracellular matrix adhesion target genes in neural and neuroendocrine YAPoff cancers (e.g., small cell lung cancer, retinoblastoma). Forced YAP/TAZ expression induces these targets, causing cytostasis in part through Integrin-αV/β5, independent of the integrin-binding RGD ligand. Other effectors of this anticancer YAP function are unknown. Here, using clustered regularly interspaced short palindromic repeats (CRISPR) screens, we link the Netrin receptor UNC5B to YAP-induced cytostasis in YAPoff cancers. Forced YAP expression induces UNC5B through TEAD DNA-binding partners, as either TEAD1/4-loss or a YAP mutation that disrupts TEAD-binding (S94A) blocks, whereas a TEAD-activator fusion (TEAD(DBD)-VP64) promotes UNC5B induction. Ectopic YAP expression also upregulates UNC5B relatives and their netrin ligands in YAPoff cancers. Netrins are considered protumorigenic, but knockout and peptide/decoy receptor blocking assays reveal that in YAPoff cancers, UNC5B and Netrin-1 can cooperate with integrin-αV/β5 to mediate YAP-induced cytostasis. These data pinpoint an unsuspected Netrin-1/UNC5B/integrin-αV/β5 axis as a critical effector of YAP tumor suppressor activity. Significance: Netrins are widely perceived as procancer proteins; however, we uncover an anticancer function for Netrin-1 and its receptor UNC5B. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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