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All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System
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Netrin-1 and UNC5B Cooperate with Integrins to Mediate YAP-Driven Cytostasis
Joel D Pearson1,2,3,4, Katherine Huang1, Louis G Dela Pena4
1Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, Canada.
Cancer Research Communications
|August 22, 2024
Summary
YAP/TAZ proteins can suppress tumors in YAPoff cancers by inducing Netrin-1/UNC5B and integrin-αV/β5, revealing a novel anticancer pathway. This discovery challenges the known roles of netrins in cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The YAP/TAZ proteins are transcriptional coactivators with opposing roles in cancer, acting as oncogenes in YAPon cancers and tumor suppressors in YAPoff cancers.
- In YAPoff cancers, YAP/TAZ are epigenetically silenced, along with their target genes involved in cell adhesion.
- Previous research indicated YAP/TAZ induce cytostasis via Integrin-αV/β5 in YAPoff cancers, but other effectors remained unknown.
Purpose of the Study:
- To identify novel effectors of YAP's tumor suppressor function in YAPoff cancers.
- To elucidate the molecular mechanisms by which YAP inhibits cancer cell proliferation in YAPoff contexts.
Main Methods:
- Utilized clustered regularly interspaced short palindromic repeats (CRISPR) screens to identify genes involved in YAP-induced cytostasis.
- Employed gene knockout, YAP mutations, TEAD-activator fusion constructs, and blocking assays to investigate gene function.
- Analyzed the expression of netrin receptors and ligands in response to YAP expression.
Main Results:
- The Netrin receptor UNC5B was identified as a key mediator of YAP-induced cytostasis in YAPoff cancers.
- YAP expression, dependent on TEAD transcription factors, induces UNC5B and related netrin pathway components.
- Contrary to their known roles, Netrin-1 and UNC5B cooperate with Integrin-αV/β5 to mediate YAP's anticancer activity.
Conclusions:
- A novel Netrin-1/UNC5B/integrin-αV/β5 signaling axis is identified as a critical effector of YAP tumor suppressor activity in YAPoff cancers.
- This study uncovers an unexpected anticancer role for Netrin-1 and UNC5B, challenging their established protumorigenic functions.
- The findings provide new insights into YAP-mediated tumor suppression and potential therapeutic targets in YAPoff cancers.
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