Abstract 2200: Multilineage plasticity in prostate cancer through expansion of stem-like luminal epithelial cells with elevated inflammatory signaling

Abstract

Abstract Lineage plasticity is a well-established mechanism of resistance to targeted therapies in lung and prostate cancer, where tumors transition from adenocarcinoma to small-cell or neuroendocrine carcinoma. Single-cell analysis of a cohort of late stage castration-resistant human prostate cancers (CRPC) revealed a greater degree of plasticity than previously appreciated, with multiple distinct neuroendocrine (NEPC), mesenchymal (EMT-like), and other subpopulations detected within single biopsies. To explore the steps responsible for initiation of this process, we utilized two genetically engineered mouse models of prostate cancer that recapitulate progression from adenocarcinoma to neuroendocrine disease. Time course studies reveal expansion of stem-like luminal epithelial cells (Sca1+, Psca+, called L2) that, based on trajectories, gave rise to at least 4 distinct subpopulations, NEPC (Ascl1+), POU2F3 (Pou2f3+), TFF3 (Tff3+) and EMT-like (Vim+, Ncam1+). Such populations are also seen in human prostate and small cell lung cancers. Furthermore, transformed L2-like cells express stem-like and gastrointestinal endoderm-like transcriptional programs, indicative of reemerging developmental plasticity programs, as well as elevated Jak/Stat, interferon, and FGF pathways. Strikingly pharmacologic inhibition of Jak/Stat and FGFR results in reversal of plasticity states and subsequent sensitivity to androgen receptor inhibitors (ARSIs). In sum, while the magnitude of multilineage heterogeneity, both within and across patients, raises considerable treatment challenges, the identification of highly plastic luminal cells as the likely source of this heterogeneity provides a target for more focused therapeutic intervention. Citation Format: Samir Zaidi, Jimmy Zhao, Joseph Chan, Roudier Martine, Kristine Wadosky, Anuradha Gopalan, Wouter Karthaus, Philip Watson, Lawrence True, Peter Nelson, Howard Scher, Michael Morris, Michael Haffner, David Goodrich, Dana Pe'er, Charles Sawyers. Multilineage plasticity in prostate cancer through expansion of stem-like luminal epithelial cells with elevated inflammatory signaling [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 2200.