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EphB4 and ephrinB2 act in opposition in the head and neck tumor microenvironment

Shilpa Bhatia1, Diemmy Nguyen1, Laurel B Darragh1

  • 1Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.

Nature Communications
|June 20, 2022
PubMed

Insights

Targeting ephrinB2 in head and neck squamous cell carcinoma (HNSCC) significantly reduces tumors. Conversely, EphB4 receptor loss accelerates HNSCC growth, highlighting ephrinB2 as a tumor promoter and EphB4 as a suppressor.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • EphB4-ephrinB2 signaling plays a complex role in cancer, posing challenges for therapeutic development.
  • Understanding this pathway's differential effects in head and neck squamous cell carcinoma (HNSCC) is crucial.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting EphB4 and ephrinB2 in HNSCC.
  • To elucidate the distinct roles of EphB4 and ephrinB2 in HNSCC tumor progression and microenvironment.

Main Methods:

  • Utilized genetically engineered mouse models for HNSCC.
  • Employed recombinant constructs, pharmacologic agonists, and antagonists to manipulate EphB4 and ephrinB2.
  • Assessed tumor growth, angiogenesis, EphA4 expression, and T regulatory cell (Treg) infiltration.

Main Results:

  • Loss of EphB4 intracellular domain on cancer cells accelerated tumor growth and angiogenesis.
  • EphB4 loss induced compensatory EphA4 upregulation and increased Treg influx, which, when targeted, reversed accelerated growth.
  • EphrinB2 knockout in cancer cells and vasculature led to maximal tumor reduction and vascular normalization.
  • EphB4 agonism showed no benefit without ephrinB2.

Conclusions:

  • EphrinB2 acts as a tumor promoter in HNSCC, while its receptor EphB4 functions as a tumor suppressor.
  • These findings offer a basis for developing novel cancer therapeutics targeting the EphB4-ephrinB2 axis in HNSCC.

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