Abstract PR004: Exploring the role of ASCL1 in neuroendocrine prostate cancer
Authors: Rodarte Kathia E. , Flores Lydia , Kandagatla Vishal , Villarreal Juan , Savage Trisha K. , Deng Su , Mu Ping , Shah Rajal B. , Oliver Trudy G. , Johnson Jane E. 
Published: June 2023

Most patients with prostate adenocarcinoma (PAd), an androgen receptor (AR) driven cancer, develop resistance to therapies targeting AR. Consequently, a portion of these patients develop neuroendocrine prostate cancer (NEPC), a rapidly progressing cancer with limited therapies and poor survival outcomes. Current research to understand the transition of PAd to NEPC suggests a model of lineage plasticity, where AR-dependent luminal tumors progress towards an AR-independent neuroendocrine lineage. Several groups have shown human NEPC tumors have lost RB1 and TP53, and in experimental models, loss of both genes mediates the transition to a neuroendocrine lineage. Notably, NEPC histology and gene expression resemble another neuroendocrine cancer, small cell lung carcinoma (SCLC), also characterized by loss of RB1 and TP53. In SCLC, transcription factor ASCL1 is required for tumor cell growth in vitro and for SCLC formation in vivo. ASCL1 is also present in NEPC tumors and in NEPC cell line models. In fact, ASCL1 was shown to regulate neuronal stem cell-like lineage programming in NEPC in vitro. We aimed to determine if ASCL1 is required in the transition of PAd to NEPC in vivo and to define its function in NEPC. To model the PAd to NEPC transition, we established genetically engineered mouse models (GEMMs) harboring loss of RB1 and TP53 with MYC overexpression (RPM) by administering adenovirus expressing Cre recombinase directly to the prostate of these GEMMs. These animals display prostate tumors with small cell histology and are heterogeneous for neuroendocrine markers such as ASCL1, NEUROD1, and INSM1. We recently determined that the concomitant loss of ASCL1 in this model (RPMA) does not stop the formation of tumors with small cell histology. Notably, a subset of the cells with small cell histology are NEUROD1+, with a higher proportion of NEUROD1+ cells present compared to the RPM model with intact ASCL1, suggesting the possibility that NEUROD1 in the same or distinct cells is compensating for the absence of ASCL1. In a separate paradigm using these same GEMMs to establish prostate organoids, we show their capacity to generate subcutaneous allograft tumors displaying mixed histology including neuroendocrine small cell features expressing ASCL1, NEUROD1, and INSM1. Strikingly, subcutaneous allografts from prostate organoids lacking ASCL1 exhibit a dramatic reduction in tumor formation efficiency, lack small cell histology including NEUROD1 and INSM1 and other neuroendocrine markers, and often result in the development of cysts rather than tumors. These results demonstrate complex functions for ASCL1 in neuroendocrine lineage programming while suggesting additional functions in supporting prostate tumor formation.

Citation Format: Kathia E. Rodarte, Lydia Flores, Vishal Kandagatla, Juan Villarreal, Trisha K. Savage, Su Deng, Ping Mu, Rajal B. Shah, Trudy G. Oliver, Jane E. Johnson. Exploring the role of ASCL1 in neuroendocrine prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR004.