Abstract 4076: Single cell RNA analysis reveals heterogeneous sub populations in aggressive variants of prostate cancer

Abstract Neuroendocrine prostate cancer (NEPC) represent an aggressive malignancy that results in poor patients outcomes. At a histological level, NEPC exhibits heterogeneous pathologies; nevertheless, the molecular features, drivers and therapeutic implications of this heterogeneity are poorly understood. Single cell technology enables the resolution needed to unveil the complex heterogeneity of NEPC that bulk RNA analysis could not previously detect. Therefore, we aim to characterize the molecular heterogeneity of NEPC at a single cell level to detect common phenotypes across patients and identify new therapeutic targets. We performed single cell RNA sequencing on a novel cohort of nine patient derived xenograft (PDX) models that recapitulate the pathological and clinical heterogeneity of NEPC. Downstream analysis of single cell data was first completed on individual samples to identify distinct subpopulations of cells within each tumor. Then, integration analysis was performed to identify common and unique neuroendocrine populations across the different tumors. We profiled the transcriptome of 19,361 cells captured from the eight NEPCs. On an individual sample analysis, we detected 3 to 8 different subpopulations in each tumor, where every subpopulation displayed distinct biological properties such as epithelial mesenchymal transition, quiescence and stemness. Data integration of all samples revealed 16 subpopulations of tumor cells across all patients, of which 10 populations were primarily unique to one patient. Enriched pathway analyses revealed heterogeneous expression of most cancer hallmarks and oncogenic pathways across subpopulations, although some pathways were common to several neuroendocrine subpopulations such as EMT, P53 and KRAS. The detection of heterogeneous subpopulations in NEPC provides novel insight into why finding effective treatments for these aggressive tumors is challenging. Future work should focus on further evaluation of common druggable pathways that are shared across NEPC subpopulations. Alternatively, efforts could look at combination therapies that could effectively target these heterogeneous tumors. Citation Format: Rosalia Quezada Urban, Shivakumar Keerthikumar, Ashlee K. Clark, Laura H. Porter, Mitchell G. Lawrence, Renea A. Taylor, Gail P. Risbridger, Roxanne Toivanen, David L. Goode. Single cell RNA analysis reveals heterogeneous sub populations in aggressive variants of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4076.