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Targeting epiregulin in the treatment-damaged tumor microenvironment restrains therapeutic resistance

Changxu Wang1, Qilai Long2, Qiang Fu3

  • 1CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.

Oncogene
|October 6, 2022
PubMed

Insights

Senescent stromal cells release epiregulin (EREG), a factor that promotes cancer drug resistance. Targeting EREG in damaged tumor microenvironments enhances treatment efficacy and offers a new biomarker for patient monitoring.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • The tumor microenvironment (TME) facilitates cancer malignancy through complex cell interactions.
  • Stromal cells within the TME can adopt a senescence-associated secretory phenotype (SASP) upon DNA damage, influencing cancer progression.

Purpose of the Study:

  • To investigate the role of soluble factors produced by senescent stromal cells in cancer progression.
  • To identify novel therapeutic targets and biomarkers within the TME.

Main Methods:

  • Investigated epiregulin (EREG) production by senescent stromal cells following genotoxicity.
  • Analyzed EREG's impact on neoplastic cells, including MARCHF4 upregulation and drug resistance.
  • Evaluated a combinational therapy targeting EREG in preclinical cancer models.
  • Assessed EREG expression in clinical samples and its correlation with patient outcomes post-chemotherapy.

Main Results:

  • Genotoxicity induces EREG expression in stromal cells via NF-κB and C/EBP signaling, enhanced by chromatin modifications.
  • Stromal EREG promotes cancer cell malignancy by upregulating MARCHF4, leading to increased drug resistance.
  • Targeting EREG in combination therapy significantly improves anti-cancer efficacy in preclinical studies.
  • EREG is detectable in tumor stroma and patient blood post-chemotherapy, serving as a potential biomarker.

Conclusions:

  • Epiregulin (EREG) is a key SASP factor secreted by senescent stromal cells that drives cancer progression and drug resistance.
  • Targeting EREG offers a promising therapeutic strategy for enhancing cancer treatment efficacy.
  • EREG represents a novel, non-invasive biomarker for assessing treatment-induced TME damage and predicting patient response.

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