Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation

Cancer Cell. 2023 Dec 11;41(12):2066-2082.e9. doi: 10.1016/j.ccell.2023.10.009. Epub 2023 Nov 22.

Abstract

Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy resistance in multiple cancer types. To gain insight into the underlying molecular events of the trans-differentiation, we perform a multi-omics time course analysis of a pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells and identify a shared developmental, arc-like, and entropy-high trajectory among all transformation model replicates. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 or ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. TFAP4 and ASCL1/2 feedback are identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, as well as connections to normal neuroendocrine cell states.

Keywords: ASCL1; ASCL2; POU2F3, TFAP4; cancer; lineage plasticity; neuroendocrine; prostate; small cell; stem-like; trans-differentiation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Carcinoma, Small Cell* / genetics
  • Cell Line, Tumor
  • Cell Transdifferentiation / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms* / genetics
  • Male
  • Prostatic Neoplasms* / genetics
  • Prostatic Neoplasms* / pathology
  • Small Cell Lung Carcinoma* / genetics
  • Transcription Factors / genetics

Substances

  • Transcription Factors
  • Basic Helix-Loop-Helix Transcription Factors
  • ASCL2 protein, human