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

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.

• Authors: João D Barros-Silva, Douglas E Linn, Ivana Steiner, Guoji Guo, Adnan Ali, Hubert Pakula, Garry Ashton, Isabel Peset, Michael Brown, Noel W Clarke, Roderick T Bronson, Guo-Cheng Yuan, Stuart H Orkin, Zhe Li, Esther Baena
• Journal: Cell reports (Cell Rep) Vol. 25 Issue 12 Pg. 3504-3518.e6 (12 18 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 30566873 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Cell Adhesion Molecules
• GPI-Linked Proteins
• LY6D protein, human

Topics

• Animals
• Biomarkers, Tumor (metabolism)
• Carcinogenesis (metabolism, pathology)
• Cell Adhesion Molecules (metabolism)
• Cell Lineage
• Disease Progression
• Epithelial Cells (metabolism)
• GPI-Linked Proteins (metabolism)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neoplastic Stem Cells (metabolism, pathology)
• Organoids (metabolism, pathology)
• Prostate (pathology)
• Prostatic Neoplasms, Castration-Resistant (metabolism, pathology)
• Regeneration
• Single-Cell Analysis