The emergence of the neuroendocrine phenotype in castration resistant prostate cancer (CRPC) is associated with poor patient prognosis. Castration-induced death of fully differentiated, androgen-sensitive PC cells might foster interactions among rare androgen-independent, poorly differentiated cancer cells and the extracellular matrix (ECM) that promotes the development of neuroendocrine PC (NEPC). Here, we investigated physical and molecular interactions between poorly differentiated PC cells with exocrine (PAC) or neuroendocrine features (PNE), which recapitulated pre-existing human CRPC-like cells, and decellularized prostate ECM. Without androgens, PAC cells and PC-derived ECM promoted in vitro invasiveness of PNE cells by inducing integrin α2 upregulation and YAP activation, indicating a cell-to-cell and cell-to-matrix contact-driven process. Inhibition of RANK/RANKL and NF-κB prevented integrin α2 upregulation in PNE cells, and integrin α2β1 and YAP inhibition also reduced PNE invasiveness. Microenvironment-conditioned PNE cells showed YAP-dependent metastatic behavior in vivo, and YAP inhibition suppressed the development of NEPC and metastasis in castration-naïve mice and of CRPC-NE in transgenic PC mice. Importantly, YAP inhibitors also restrained the growth of human CRPC organoids. These findings unveil mechanisms of NEPC development and implicate the integrin α2-YAP axis as a therapeutic target in PC patients receiving androgen-deprivation therapy.
Cancer research. 2026 Mar 05 [Epub ahead of print]
Arianna Brevi, Marco Lorenzoni, Sara Caputo, Yasutaka Yamada, Matteo Grioni, Laura L Cogrossi, Laura Martinez-Vidal, Valeria Cassina, Deborah Cipria, Chiara Venegoni, Paola Zordan, Vittoria Matafora, Anna S Tascini, Nazario P Tenace, Riccardo Campanile, Vito Cucchiara, Valeria Pinna, Elena Jachetti, Rossella Galli, Angela Bachi, Maurizio Colecchia, Alberto Briganti, Massimo Freschi, Francesco Mantegazza, Angelo Lombardo, Francesca Demichelis, Himisha Beltran, Massimo Alfano, Matteo Bellone
University of California, San Diego La Jolla, California United States., Fondazione IRCCS Istituto Nazionale dei Tumori Milan, Milan Italy., San Raffaele Scientific Institute Milan Italy., Dana-Farber Cancer Institute Boston, MA United States., IRCCS Ospedale San Raffaele Milan Italy., University of Milano-Bicocca Italy., San Raffaele Telethon Institute for Gene Therapy Italy., IFOM ETS - The AIRC Institute of Molecular Oncology Milan Italy., IRCCS Ospedale San Raffaele Milano Italy., University of Milano - Bicocca Vedano al Lambro Italy., San Raffaele Scientific Institute Italy., Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (Italy) Milan Italy., IRCCS Ospedale San Raffaele Milano, Italy Italy., University of Milano-Bicocca Vedano al Lambro, MB Italy., San Raffaele Scientific Institute Milano, MI Italy., University of Trento Trento Italy.