2. Academic Validation
  3. Intercepting YAP Activation in Prostate Cancer Blocks Neuroendocrine Progression

Intercepting YAP Activation in Prostate Cancer Blocks Neuroendocrine Progression

  • Cancer Res. 2026 Jun 15;86(12):2860-2877. doi: 10.1158/0008-5472.CAN-25-2704.
Arianna Brevi # 1,  Marco Lorenzoni # 1,  Sara Caputo 1,  Yasutaka Yamada 2,  Matteo Grioni 1,  Laura L Cogrossi 1 3,  Laura Martinez-Vidal 4,  Valeria Cassina 5,  Deborah Cipria 6,  Chiara Venegoni 4,  Paola Zordan 1,  Vittoria Matafora 7,  Anna S Tascini 8,  Nazario P Tenace 9,  Riccardo Campanile 5,  Vito Cucchiara 4,  Valeria Pinna 10,  Elena Jachetti 10,  Rossella Galli 11,  Angela Bachi 7,  Maurizio Colecchia 3 9,  Alberto Briganti 3 4,  Massimo Freschi 9,  Francesco Mantegazza 5,  Angelo Lombardo 3 6,  Francesca Demichelis 12,  Himisha Beltran 2,  Massimo Alfano 4,  Matteo Bellone 1
Affiliations

Affiliations

  • 1 Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 3 Vita-Salute San Raffaele University, Milan, Italy.
  • 4 Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy.
  • 5 School of Medicine and Surgery, BioNanoMedicine Center NANOMIB, Università di Milano-Bicocca, Vedano al Lambro, Italy.
  • 6 San Raffaele Telethon Institute for Gene Therapy, IRCCS Ospedale San Raffaele, Milan, Italy.
  • 7 Proteomics Unit, IFOM-FIRC Institute of Molecular Oncology, Milan, Italy.
  • 8 Center for Omics Sciences, IRCCS Ospedale San Raffaele, Milan, Italy.
  • 9 Unità Operativa Anatomia Patologica, IRCCS Ospedale San Raffaele, Milan, Italy.
  • 10 Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
  • 11 Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.
  • 12 Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
  • # Contributed equally.
PMID: 41784633 DOI: 10.1158/0008-5472.CAN-25-2704
Abstract

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 prostate Cancer cells might foster interactions among rare androgen-independent, poorly differentiated Cancer cells and the extracellular matrix (ECM) that promotes the development of neuroendocrine prostate Cancer (NEPC). In this study, we investigated physical and molecular interactions between poorly differentiated prostate Cancer cells with exocrine (PAC) or neuroendocrine features (PNE), which recapitulated preexisting human CRPC-like cells, and decellularized prostate ECM. Without androgens, PAC cells and prostate cancer-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 neuroendocrine CRPC in transgenic mice with prostate Cancer. 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 patients with prostate Cancer receiving androgen deprivation therapy.

Significance: Targeting signaling pathways activated by interactions between poorly differentiated neuroendocrine and exocrine prostate Cancer cells and the surrounding ECM suppresses NEPC development and metastasis.

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