Single Cell Analysis Identified Ly6d As A Novel Marker Of Castration-Resistant Multipotent Luminal Progenitors

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LAThe cellular origin of castration-resistant prostate cancer (CRPC) remains largely unsolved. We compared single-cell expression profiles of prostate cells sorted from hormone-naive and castrated mice. Our single-cell analysis reveals that the prostate luminal lineage is highly heterogeneous. A subset of prostate cells in the luminal lineage characterized by high expression levels of luminal lineage markers including cytokeratin 8 (Krt8) and androgen receptor (Ar) genes, as well as prostate stem/progenitor marker genes (e.g., Trop2/Tacstd2, Sca1/Ly6a), and intermediate levels of basal genes (e.g. Trp63, Krt5), is enriched upon castration. We validated LY6D as a novel marker of castration-resistant (CR) multipotent luminal progenitor. Organoid culture revealed that LY6D+ prostate cells, including LY6D+ prostate luminal cells, were enriched with multipotent organoid-forming cells under androgen-deprivation. Lineage-tracing using Krt8-CreER mice revealed that in wild-type mice, LY6D+ CR luminal cells appeared to produce LY6D- luminal cells upon regeneration; however, when under the Pten-loss background, LY6D+ Pten-null luminal cells gave rise to LY6D+ luminal cancer cells. Furthermore, upon induced loss of Pten, prostate cancers originating from Krt8+ CR luminal cells were LY6D+ high-grade and were more advanced than those originating from hormone-naive luminal cells. Lastly, in prostate cancer patients, LY6D amplification/upregulation correlates with advanced disease. Overall, our results uncover the luminal lineage heterogeneity and identify LY6D as a novel tumor-initiating cell marker of CRPC.Citation Format: Douglas E. Linn, Joao Barros-Silva, Guoji Guo, Michael Brown, Garry Ashton, Noel W. Clarke, Guo-Cheng Yuan, Stuart H. Orkin, Esther Baena, Zhe Li. Single cell analysis identified LY6D as a novel marker of castration-resistant multipotent luminal progenitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-275.