The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1

Romero, Rodrigo, Chu, Tinyi, González-Robles, Tania J, Smith, Perianne, Xie, Yubin, Kaur, Harmanpreet, Yoder, Sara, Zhao, Huiyong, Mao, Chenyi, Kang, Wenfei, Pulina, Maria V, Lawrence, Kayla E, Gopalan, Anuradha, Zaidi, Samir, Yoo, Kwangmin, Choi, Jungmin, Fan, Ning, Gerstner, Olivia, Karthaus, Wouter R, DeStanchina, Elisa, Ruggles, Kelly V, Westcott, Peter MK, Chaligné, Ronan, Pe'er, Dana, Sawyers, Charles L (April 2024) The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1. bioRxiv.

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Abstract

Lineage plasticity is a recognized hallmark of cancer progression that can shape therapy outcomes. The underlying cellular and molecular mechanisms mediating lineage plasticity remain poorly understood. Here, we describe a versatile in vivo platform to identify and interrogate the molecular determinants of neuroendocrine lineage transformation at different stages of prostate cancer progression. Adenocarcinomas reliably develop following orthotopic transplantation of primary mouse prostate organoids acutely engineered with human-relevant driver alterations (e.g., Rb1-/-; Trp53-/-; cMyc+ or Pten-/-; Trp53-/-; cMyc+), but only those with Rb1 deletion progress to ASCL1+ neuroendocrine prostate cancer (NEPC), a highly aggressive, androgen receptor signaling inhibitor (ARSI)-resistant tumor. Importantly, we show this lineage transition requires a native in vivo microenvironment not replicated by conventional organoid culture. By integrating multiplexed immunofluorescence, spatial transcriptomics and PrismSpot to identify cell type-specific spatial gene modules, we reveal that ASCL1+ cells arise from KRT8+ luminal epithelial cells that progressively acquire transcriptional heterogeneity, producing large ASCL1+;KRT8- NEPC clusters. Ascl1 loss in established NEPC results in transient tumor regression followed by recurrence; however, Ascl1 deletion prior to transplantation completely abrogates lineage plasticity, yielding adenocarcinomas with elevated AR expression and marked sensitivity to castration. The dynamic feature of this model reveals the importance of timing of therapies focused on lineage plasticity and offers a platform for identification of additional lineage plasticity drivers.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > prostate cancer diseases & disorders > cancer > cancer types
CSHL Authors:	Westcott, Peter
Communities:	CSHL labs > Westcott lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	11 April 2024
Date Deposited:	26 Apr 2024 14:59
Last Modified:	26 Apr 2024 14:59
PMCID:	PMC11030418
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41519

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