Baker, Martin J; Zhang, Suli; Zhang, Daniel; Searle, Joshua; Lal, Priti; Vlaar, Cornelis P; Dharmawardhane, Suranganie; ... Cooke, Mariana; + view all Baker, Martin J; Zhang, Suli; Zhang, Daniel; Searle, Joshua; Lal, Priti; Vlaar, Cornelis P; Dharmawardhane, Suranganie; Abba, Martín C; Kazanietz, Marcelo G; Cooke, Mariana; - view fewer (2025) VAV2 drives EGFR-mediated Rac1 responses in prostate cancer. Molecular Cancer Research OF1-OF15. 10.1158/1541-7786.MCR-24-0957. (In press).

Text mcr-24-0957.pdf - Accepted Version Access restricted to UCL open access staff until 19 April 2026. Download (17MB)

Abstract

The small G-protein Rac1 is a central player in cancer progression and metastatic dissemination. Rac1 has been established as a bona fide effector of receptor tyrosine kinases, acting as a signaling node for motility, invasiveness, mitogenesis, and gene expression. Previous studies demonstrated that Rac1 is hyperactivated in aggressive cellular models of prostate cancer. Here, we show that CRISPR/Cas9-based knockout of Rac1 leads to impaired prostate cancer cell proliferation and migration. Rac1-null cells display profound alterations in transcriptional programs, particularly those associated with cell adhesion and extracellular matrix (ECM) regulation. Combined expression profiling and unbiased RNAi screening of Rac1 Guanine nucleotide Exchange Factors (Rac-GEFs) identified VAV2 as the foremost mediator of epidermal growth factor (EGF)-induced GTP loading onto Rac1 in prostate cancer cells. VAV2 depletion from prostate cancer cells significantly reduced their proliferative and migratory capacities without affecting the expression of Rac1-regulated genes, suggesting that VAV2 controls a discrete subset of Rac1-dependent cellular responses. Immunohistochemical assessment in human prostate biopsies showed significant VAV2 overexpression in tumor areas. Bioinformatic analysis revealed a strong correlation between VAV2 expression and poor clinical prognosis. In addition to uncovering a prominent role for VAV2-Rac1 as an effector pathway mediating EGFR-driven proliferative and migratory responses in prostate cancer cells, our findings underscore the potential prognostic value of VAV2 in human prostate cancer progression. Implications: This study highlights VAV2's central role in prostate cancer cell proliferation and migration and its potential prognostic value in disease progression.

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