Single-cell transcriptional regulation and genetic evolution of neuroendocrine prostate cancer

Ziwei Wang, Tao Wang, Danni Hong, Baijun Dong, Yan Wang, Huaqiang Huang, Wenhui Zhang, Bijun Lian, Boyao Ji, Haoqing Shi, Min Qu, Xu Gao, Daofeng Li, Colin Collins, Gonghong Wei, Chuanliang Xu, Hyung Joo Lee, Jialiang Huang, Jing Li

Research output: Contribution to journalArticlepeer-review

Abstract

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer, with a 10% five-year survival rate. However, little is known about its origin and the mechanisms governing its emergence. Our study characterized ADPC and NEPC in prostate tumors from 7 patients using scRNA-seq. First, we identified two NEPC gene expression signatures representing different phases of trans-differentiation. New marker genes we identified may be used for clinical diagnosis. Second, integrative analyses combining expression and subclonal architecture revealed different paths by which NEPC diverges from the original ADPC, either directly from treatment-naïve tumor cells or from specific intermediate states of treatment-resistance. Third, we inferred a hierarchical transcription factor (TF) network underlying the progression, which involves constitutive regulation by ASCL1, FOXA2, and selective regulation by NKX2-2, POU3F2, and SOX2. Together, these results defined the complex expression profiles and advanced our understanding of the genetic and transcriptomic mechanisms leading to NEPC differentiation.

Original languageEnglish
Article number104576
JournaliScience
Volume25
Issue number7
DOIs
StatePublished - Jul 15 2022

Keywords

  • Cancer
  • Cancer systems biology
  • Transcriptomics

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