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Updated: Aug 23, 2025

Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture
10:38

Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture

Published on: November 22, 2019

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FOXA2 drives lineage plasticity and KIT pathway activation in neuroendocrine prostate cancer

Ming Han1, Fei Li1, Yehan Zhang1

  • 1State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.

Cancer Cell
|November 4, 2022
PubMed

Insights

Prostate cancer can switch to neuroendocrine prostate cancer (NEPC) due to therapeutic resistance. Researchers found FOXA2 drives this transition, offering a new therapeutic target for NEPC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Prostate cancer lineage plasticity, specifically adeno-to-neuroendocrine transition, is a key mechanism of therapeutic resistance.
  • Identifying molecular drivers of this transition is crucial for developing effective treatments for castration-resistant neuroendocrine prostate cancer (NEPC).

Purpose of the Study:

  • To investigate the cellular and molecular mechanisms driving prostate cancer adeno-to-neuroendocrine lineage transition.
  • To identify potential pharmacological strategies to overcome resistance in NEPC.

Main Methods:

  • Single-cell multiomics analyses of 107,201 cells from genetically engineered mouse prostate cancer models.
  • Time-series analysis of tumor evolution mirroring human disease progression.
  • Gene knockdown experiments (Foxa2) and pharmacologic inhibition of the KIT pathway.

Main Results:

  • FOXA2 was identified as a key orchestrator of the adeno-to-neuroendocrine transition, with its expression induced by androgen deprivation.
  • Foxa2 knockdown reversed the lineage transition.
  • The KIT pathway was found to be directly regulated by FOXA2 and activated in NEPC.
  • Pharmacologic inhibition of the KIT pathway suppressed NEPC tumor growth in mouse and human models.

Conclusions:

  • FOXA2 drives adeno-to-neuroendocrine lineage plasticity in prostate cancer.
  • Targeting the FOXA2-KIT pathway presents a promising therapeutic strategy for castration-resistant NEPC.
Keywords:
Foxa1Foxa2KITclinical-grade inhibitorspharmacological strategyprostate cancer lineage plasticitysingle-cell multiomicstherapeutic resistance

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