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Dll1-Mediated Notch Signaling Drives Tumor Cell Cross-talk with Cancer-Associated Fibroblasts to Promote

Ajeya Nandi1, Rahul Debnath1, Anupma Nayak2

  • 1Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, Pennsylvania.

Cancer Research
|August 25, 2022
PubMed
Abstract

Insights

Notch signaling activation by Dll1+ breast cancer cells promotes fibroblast Wnt ligand secretion, driving radioresistance and metastasis. Targeting this pathway offers new therapeutic strategies for breast cancer treatment.

Area of Science:

  • Oncology
  • Cell Biology
  • Cancer Signaling Pathways

Background:

  • Notch signaling plays a role in cancer progression.
  • Cancer-associated fibroblasts (CAFs) influence the tumor microenvironment.
  • Radioresistance and metastasis are key challenges in breast cancer treatment.

Purpose of the Study:

  • To investigate the role of Dll1+ breast cancer cells in activating Notch signaling in CAFs.
  • To determine the downstream effects of this activation on Wnt ligand secretion.
  • To elucidate the contribution of this pathway to breast cancer radioresistance and metastasis.

Main Methods:

  • Co-culture systems of Dll1+ breast cancer cells and CAFs.
  • Analysis of Notch signaling pathway activation.
  • Measurement of Wnt ligand secretion.
  • Assessment of β-catenin activity.
  • Evaluation of radioresistance and metastatic potential in vitro and in vivo models.

Main Results:

  • Dll1+ breast cancer cells were found to activate Notch signaling in CAFs.
  • This activation led to increased secretion of Wnt ligands by CAFs.
  • Elevated Wnt signaling, driven by β-catenin, correlated with enhanced radioresistance and metastasis.
  • Targeting the Notch-Wnt axis demonstrated potential to overcome these challenges.

Conclusions:

  • The Dll1-Notch-Wnt axis represents a critical mechanism in breast cancer progression.
  • Activation of Notch signaling in CAFs by cancer cells promotes a pro-tumorigenic microenvironment.
  • This crosstalk confers radioresistance and enhances metastatic potential.
  • Inhibition of this pathway presents a promising therapeutic strategy for improving breast cancer outcomes.

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