Benign prostatic hyperplasia (BPH) is the most common urologic condition in elderly men, characterized by the reactivation of developmental programs such as prostatic budding and branching. However, the molecular mechanisms underlying this reactivation in BPH remain unclear. In this study, we identified TIAM1 (T-lymphoma invasion and metastasis-inducing protein-1) as a critical regulator of prostatic budding and branching. By generating an unbiased BPH transcriptomic signature from patient datasets, we discovered an upregulation of TIAM1, which was subsequently validated at the protein level. Functional assays using organoid cultures derived from human prostatic cell lines revealed that TIAM1 is essential for prostatic budding and branching. Additionally, the BPH transcriptomic signature identified NSC23766, a small molecule inhibitor of TIAM1-RAC1 signaling, as a therapeutic proof-of-concept agent for BPH. Genetic knockdown of TIAM1 in human prostatic cell lines markedly reduced organoid branching, an effect mirrored by administration of NSC23766. The translational relevance of these findings is underscored by the growth inhibition observed in patient-derived BPH organoids treated with NSC23766. In conclusion, our findings identify TIAM1 as a key driver of prostatic branching and growth, and suggest that targeting TIAM1-RAC1 signaling could be a promising therapeutic strategy for BPH.
JCI insight. 2025 May 20 [Epub ahead of print]
Hamed Khedmatgozar, Sayanika Dutta, Michael Dominguez, Murugananthkumar Raju, Girijesh Kumar Patel, Daniel Latour, Melanie Johnson, Mohamed Fokar, Irfan Warraich, Allan Haynes, Barry J Maurer, Werner de Riese, Luis Brandi, Robert J Matusik, Srinivas Nandana, Manisha Tripathi
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, United States of America., Center for Biotechnology and Biochemistry, Texas Tech University, Lubbock, United States of America., Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, United States of America., Department of Urology, Texas Tech University Health Sciences Center, Lubbock, United States of America., Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, United States of America., Department of Urology, Vanderbilt University Medical Center, Nashville, United States of America.