Related Experiment Video

Updated: Jul 19, 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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ASCL1 is activated downstream of the ROR2/CREB signaling pathway to support lineage plasticity in prostate cancer

Nakisa Tabrizian1, Shaghayegh Nouruzi1, Cassandra Jingjing Cui1

  • 1Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.

Cell Reports
|August 8, 2023
PubMed

Insights

Androgen receptor (AR) pathway inhibitors can cause prostate cancer relapse through lineage plasticity. Researchers found that ROR2 activation drives this resistance by promoting stem-cell-like networks, suggesting ROR2 as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Lineage plasticity is a key mechanism of therapy-induced drug resistance in cancer.
  • Prostate cancer treated with androgen receptor (AR) pathway inhibitors can relapse due to loss of AR signaling and a shift to an alternate cellular program.
  • The precise molecular mechanisms driving lineage plasticity under AR-targeted therapy pressure remain incompletely understood.

Purpose of the Study:

  • To investigate the molecular signaling pathways, particularly receptor tyrosine kinases (RTKs), involved in driving lineage plasticity during AR-targeted therapy in prostate cancer.
  • To identify novel therapeutic targets that can overcome or reverse therapy-induced lineage plasticity and drug resistance.

Main Methods:

  • A comprehensive survey of receptor tyrosine kinases (RTKs) was performed in the context of AR pathway inhibition.
  • Analysis focused on identifying upregulated RTKs associated with the development of lineage plasticity.
  • Mechanistic studies explored the downstream signaling pathways activated by identified RTKs, including ERK/CREB and the transcription factor ASCL1.

Main Results:

  • Receptor tyrosine kinase 2 (ROR2) was identified as the top upregulated RTK following AR pathway inhibition.
  • ROR2 activation was found to promote stem-cell-like and neuronal signaling networks, contributing to lineage plasticity.
  • ROR2 was shown to activate the ERK/CREB signaling pathway, which modulates the expression of the lineage commitment transcription factor ASCL1.

Conclusions:

  • ROR2 plays a critical role in mediating androgen receptor inhibitor-induced lineage plasticity in prostate cancer.
  • Targeting ROR2 may represent a viable strategy to reverse the plastic phenotype and re-sensitize tumors to AR pathway inhibitors.
  • Understanding ROR2-mediated signaling offers new avenues for overcoming treatment resistance in prostate cancer.
Keywords:
ASCL1CP: CancerCREBROR2cellular plasticityneuroendocrineprostate cancer

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