Single-Cell Analysis Identifies LY6D as a Marker Linking Castration-Resistant Prostate Luminal Cells to Prostate Progenitors and Cancer

Research output: Contribution to journalArticle

  • External authors:
  • João D Barros-Silva
  • Douglas E Linn
  • Ivana Steiner
  • Guoji Guo
  • Hubert Pakula
  • Garry Ashton
  • Isabel Peset
  • Noel W Clarke
  • Roderick T Bronson
  • Guo-Cheng Yuan
  • Stuart H Orkin
  • Zhe Li
  • Esther Baena

Abstract

The exact identity of castrate-resistant (CR) cells and their relation to CR prostate cancer (CRPC) is unresolved. We use single-cell gene profiling to analyze the molecular heterogeneity in basal and luminal compartments. Within the luminal compartment, we identify a subset of cells intrinsically resistant to castration with a bi-lineage gene expression pattern. We discover LY6D as a marker of CR prostate progenitors with multipotent differentiation and enriched organoid-forming capacity. Lineage tracing further reveals that LY6D+ CR luminal cells can produce LY6D- luminal cells. In contrast, in luminal cells lacking PTEN, LY6D+ cells predominantly give rise to LY6D+ tumor cells, contributing to high-grade PIN lesions. Gene expression analyses in patients' biopsies indicate that LY6D expression correlates with early disease progression, including progression to CRPC. Our studies thus identify a subpopulation of luminal progenitors characterized by LY6D expression and intrinsic castration resistance. LY6D may serve as a prognostic maker for advanced prostate cancer.

Bibliographical metadata

Original languageEnglish
Pages (from-to)3504-3518.e6
JournalCell Reports
Volume25
Issue number12
DOIs
Publication statusPublished - 18 Dec 2018