Abstract 1116: Identifying neuroendocrine prostate cancer drivers using in vivo forward genetics

Abstract

Abstract Prostate cancer (PC) is the malignancy with the highest incidence worldwide in males. Although localized disease can be effectively treated and usually has a favorable prognosis, progression to metastasis results in high mortality rates as current treatment modalities are not yet curative. The standard of care for advanced PC is hormonal therapy, termed Androgen Deprivation Therapy (ADT). Unfortunately, ADT typically elicits the emergence of a lethal phenotype, termed Castration-Resistant Prostate Cancer (CRPC), which is treatment-resistant and frequently gives rise to a highly aggressive variant with features of neuroendocrine (NE) differentiation, known as Neuroendocrine PC (NEPC). There is no cure for NEPC, thus identifying drivers that lead to its emergence is of paramount importance. We used the Sleeping Beauty (SB) transposon system to perform a forward genetic screening on Genetically-Engineered Mouse Models (GEMMs) of CRPC that are known to develop NEPC under ADT pressure. SB transposon activation generated tumors with an accelerated growth phenotype and increased metastasis incidence compared to non-activated controls. Notably, several tumors presented histological features of NEPC. We sequenced SB transposon integration sites on tumors’ genomes to identify recurrent patterns suggesting genes responsible for phenotype acceleration and NEPC differentiation. Recently, we generated and assembled a set of >100 GEMM-derived tumors, that recapitulate a broad spectrum of PC disease states, to reverse-engineer a network of regulatory proteins. We used this network on RNA-Seq data collected from SB-activated tumors to identify Master Regulator (MR) proteins that are specifically associated with NEPC emergence. Cross-species network analysis of patient-specific MRs activity conservation between patient and our mouse cohorts, aligned NEPC patients to mice tumors with NE features, corroborating our study's clinical relevance. We performed an integrative network analysis that links genomic events as generated by SB transposon integrations to downstream regulatory programs implemented by MR proteins. This analysis prioritized Sirt1 as upstream modulator of NEPC MRs activity. Activation of SIRT1 in human adenocarcinoma PC cells induced NE-like phenotype, while SIRT1 inhibitor in NEPC cells reduced tumor aggressiveness. In summary, we used in vivo models of prostate cancer to elucidate molecular drivers of NEPC, a lethal variant that is treatment-resistant. Integrative network data analysis prioritized Sirt1 as driver of NEPC emergence and was validated in vivo. Citation Format: Alessandro Vasciaveo, Francisca Nunes De Almeida, Min Zou, Matteo Di Bernardo, Andrea Califano, Cory Abate-Shen. Identifying neuroendocrine prostate cancer drivers using in vivo forward genetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1116.