Netrin-1 and UNC5B Cooperate with Integrins to Mediate YAP-Driven Cytostasis - CRCL-Apoptose, cancer et développement
Journal Articles Cancer Research Communications Year : 2024

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

Abstract

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 anti-cancer YAP function are unknown. Here, using 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 pro-tumorigenic, 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.
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Dates and versions

hal-04676524 , version 1 (23-08-2024)

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Joel D Pearson, Katherine Huang, Dela Pena, Benjamin Ducarouge, Patrick Mehlen, et al.. Netrin-1 and UNC5B Cooperate with Integrins to Mediate YAP-Driven Cytostasis. Cancer Research Communications, inPress, ⟨10.1158/2767-9764.CRC-24-0101⟩. ⟨hal-04676524⟩
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