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Updated: Jun 20, 2025

An Orthotopic Murine Model of Human Prostate Cancer Metastasis
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An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Published on: September 18, 2013

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Notch signaling suppresses neuroendocrine differentiation and alters the immune microenvironment in advanced prostate

Sheng-Yu Ku1, Yanqing Wang2, Maria Mica Garcia1

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

The Journal of Clinical Investigation
|July 18, 2024
PubMed

Insights

Notch signaling suppresses neuroendocrine prostate cancer progression. Activating Notch in advanced prostate cancer models reversed the neuroendocrine phenotype, promoting a less aggressive state and enhancing anti-tumor immunity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Notch signaling exhibits context-dependent roles in cancer, acting as oncogenic or tumor-suppressive.
  • In early prostate cancer, Notch signaling can be oncogenic, but its role in advanced stages, particularly neuroendocrine prostate cancer (NEPC), is less understood.

Purpose of the Study:

  • To investigate the function of Notch signaling in advanced prostate cancer, specifically its role in the transition to neuroendocrine prostate cancer (NEPC).
  • To determine if Notch pathway activation can reverse the NEPC phenotype and influence the tumor microenvironment (TME).

Main Methods:

  • Analysis of Notch pathway expression during prostate cancer progression from adenocarcinoma to NEPC.
  • Activation of Notch signaling in preclinical models of NEPC (Rb1/Trp53-deficient).
  • Assessment of phenotypic changes, lineage marker expression, and immune cell infiltration following Notch activation.

Main Results:

  • Notch pathway is significantly downregulated during prostate cancer progression to NEPC.
  • Activation of Notch signaling in NEPC models induced a phenotypic switch to a more indolent, non-NE state with glandular features.
  • Notch activation led to increased expression of luminal markers, upregulation of MHC and type I IFN, and enhanced immune cell infiltration.

Conclusions:

  • Notch signaling acts as a tumor suppressor in advanced NEPC, inhibiting neuroendocrine differentiation.
  • Notch pathway activation can reverse the aggressive NEPC phenotype and remodel the TME towards an anti-tumor immune response.
  • These findings highlight Notch signaling's role in lineage plasticity and offer potential therapeutic strategies for NEPC.
Keywords:
OncologyProstate cancer

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