Temporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer. Academic Article uri icon

Overview

abstract

  • Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.

publication date

  • June 7, 2021

Research

keywords

  • Adenocarcinoma
  • Carcinoma, Neuroendocrine
  • Gene Expression Regulation, Neoplastic
  • Prostate
  • Prostatic Neoplasms
  • Receptors, Androgen

Identity

PubMed Central ID

  • PMC8185096

Scopus Document Identifier

  • 85107547631

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-12-4213

PubMed ID

  • 34099734

Additional Document Info

volume

  • 12

issue

  • 1