Abstract PR007: ERG-driven luminal prostate cancers emerge from Ck5+/Nkx3.1+ basal cells

Abstract

Abstract TMPRSS2-ERG translocations are initiating lesions in nearly 50% of human prostate adenocarcinomas, often in conjunction with PTEN loss. In mice, prostate-specific expression of ERG using a Probasin-Cre driver (Pb-Cre4) is sufficient to induce invasive Ck8+ luminal adenocarcinoma with high penetrance in the context of Pten loss. Because TMPRSS2 expression in the human prostate is androgen-regulated and thereby largely restricted to luminal epithelial cells, it has been assumed that luminal cells are the likely cell of origin for TMPRSS2-ERG positive prostate cancers. To gain further support for this hypothesis, we examined the early stages of luminal adenocarcinoma initiation in the Pb-Cre ERG/Pten model at a single cell level. To our surprise, we found a highly proliferative population of ERG+ Ck5+ (a putative basal marker) cells that are enriched at the invasive front in a background of more canonical ERG+/Ck8+/Ck5- luminal tumor cells. We next performed lineage tracing experiments using Ck5-, Ck8- as well as Nkx3.1-Cre drivers, introduced via viral injection or tamoxifen induction, which collectively support the hypothesis that ERG-driven tumors originate in a subset of basal cells defined by Ck5+/Nkx3.1+. This conclusion is further supported by orthotopic transplantation of freshly isolated primary mouse prostate basal (Cd49f high) or luminal (Cd24 high) cells showing that ERG+/Ck8+ tumors arise preferentially from basal cells following ex vivo ERG/Pten activation. Time course experiments in organoids and in vivo show that ERG promotes Ck8+ luminal differentiation from highly proliferative Ck5+ cells, progressing through a Ck5+/Ck8+ intermediate cell state. Collectively, these data implicate a tumor initiating cell population defined by a mix of basal (Ck5) and luminal (Nkx3.1) markers that, under the influence of ERG expression, can expand and invade while retaining full luminal differentiation potential. Our results also suggest that widely held assumptions regarding luminal-specific expression of canonical markers such as Nkx3.1 and Probasin may need revision. Citation Format: Weiran Feng, Erik Ladewig, Nazifa Salsabeel, Huiyong Zhao, Young Sun Lee, Anuradha Gopalan, Hanzhi Luo, Wenfei Kang, Ning Fan, Eric Rosiek, Ignas Masilionis, Katia Manova-Todorova, Ronan Chaligné, Elisa de Stanchina, Brett S. Carver, Yu Chen, Dong Gao, Christina S. Leslie, Charles L. Sawyers. ERG-driven luminal prostate cancers emerge from Ck5+/Nkx3.1+ basal cells [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 PR007.