Although most prostate tumors are relatively indolent, advanced disease can progress to aggressive, often lethal variants, including neuroendocrine prostate cancer (NEPC). To identify drivers of aggressive prostate cancer, we used Sleeping Beauty (SB) transposon mutagenesis in a mouse model having prostate-specific loss of Pten and Tp53 (NPp53 mice). Compared with control NPp53-SB(-) mice, experimental NPp53-SB(+) mice developed more aggressive tumors with increased metastasis. Notably, NPp53-SB(+) mice exhibited NEPC phenotypes with transcriptomic features that recapitulate human NEPC. Analysis of recurrent common insertion sites (CIS) and associated genes (CIS genes) identified genes differentially expressed between NEPC and non-NEPC tumors. Analysis of NEPC-enriched CIS genes by cross-species integration of genomic and transcriptomic data prioritized sirtuin 1 (Sirt1) as a candidate mechanistic determinant of NEPC. Gain- and loss-of-function studies in human prostate cancer cells and mouse NEPC organoids confirmed that SIRT1 promotes NEPC, while pharmacological inhibition suppresses it. Thus, integration of cross-species analyses with an unbiased forward genetic screen uncovered novel drivers of NEPC.
The Journal of experimental medicine. 2026 May 28 [Epub]
Francisca Nunes de Almeida, Alessandro Vasciaveo, Arianna Giacobbe, Matteo Di Bernardo, Min Zou, Ainsley Mike Antao, Simone de Brot, Antonio Rodriguez-Calero, Alexander Chui, Alexander L E Wang, Nicolas Floc'h, Jaime Y Kim, Soonbum Park, Stephanie N Afari, Timur Mukhammadov, Nicholas Ortega, Sai Sampath Josyula, Juan Martin Arriaga, Jingqiang Wang, Jinqiu Lu, Michael M Shen, Mark A Rubin, Andrea Califano, Cory Abate-Shen
Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA., Department of Systems Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA., COMPATH, Institute of Animal Pathology, University of Bern , Bern, Switzerland., Department of Biomedical Research, University of Bern, Bern, Switzerland.