In Vivo Screen in Benign Prostate Epithelium Identifies Loss of α-Catenin as a Driver of Metastasis and Androgen Insensitivity

Comer M, Hart A, Lee Yu H, Nazlamova L, Milne-Clark T, Thomas J, Mahalingam V, Dobson L, Robb T, Palma-Reis Goldie F, Hautaviita K, Elwakeel A, Field S, Patikas N, Barber H, Cheung M, Machesky L, Fernandez-Vega I, Metzakopian E, Bradley A, Dev H, de la Rosa J.

Preprint available at SSRN

Therapy-refractory progression in prostate cancer is driven by context-specific combinations of tumour-suppressor loss and lineage plasticity, yet causal interactions in vivo remain poorly defined. We established an orthotopic, transplant-based CRISPR screening platform that initiates tumours from normal primary prostate epithelial cells and permits pooled functional interrogation in immunocompetent mice. Using a focused tumour-suppressor library in a Pten-deficient background, we identified Ctnna1 (α-catenin) loss as a recurrent driver of tumour growth and metastasis. Single-cell and bulk RNA-sequencing across mouse tissues revealed induction of epithelial–mesenchymal transition upon Ctnna1 loss and upregulation of classical oncogenic drivers such as Myc and Kras. In vitro, LNCaP CTNNA1 knockout cells displayed altered morphology, impaired focal adhesion formation, and increased motility. CTNNA1 loss reduced AR chromatin recruitment, diminished androgen-response reporter activity and lowered expression of canonical androgen receptor (AR) targets, consistent with cistromic reprogramming. While phospho-AKT signalling was largely unchanged, YAP1 showed increased nuclear localisation with induction of YAP/TAZ-responsive genes, consistent with mechanotransduction-driven activation. Functionally, CTNNA1 knockout decreased sensitivity to the AR antagonist enzalutamide with transcriptional profiles showing a shift from AR signalling to stem-like and neuroendocrine programs. Together, these data position α-catenin as a prostate-relevant junctional hub coupling adherens-junction integrity to YAP/TEAD-driven lineage plasticity, metastatic competence and reduced androgen-pathway dependence, while preserving therapeutic vulnerability to PI3K–AKT blockade in advanced disease.