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

Author

Listed:
  • Shilpa Bhatia

    (University of Colorado Denver)

  • Diemmy Nguyen

    (University of Colorado Denver)

  • Laurel B. Darragh

    (University of Colorado Denver)

  • Benjamin Van Court

    (University of Colorado Denver)

  • Jaspreet Sharma

    (University of Colorado Denver)

  • Michael W. Knitz

    (University of Colorado Denver)

  • Miles Piper

    (University of Colorado Denver)

  • Sanjana Bukkapatnam

    (University of Colorado Denver)

  • Jacob Gadwa

    (University of Colorado Denver)

  • Thomas E. Bickett

    (University of Colorado Denver)

  • Shiv Bhuvane

    (University of Colorado Denver)

  • Sophia Corbo

    (University of Colorado Denver)

  • Brian Wu

    (University Health Network and University of Toronto)

  • Yichien Lee

    (Georgetown University Medical Center)

  • Mayumi Fujita

    (University of Colorado Denver, Anschutz Medical Campus)

  • Molishree Joshi

    (University of Colorado Denver, Anschutz Medical Campus)

  • Lynn E. Heasley

    (University of Colorado Denver)

  • Robert L. Ferris

    (University of Pittsburgh
    University of Pittsburgh School of Medicine
    UPMC Hillman Cancer Center)

  • Olga Rodriguez

    (Georgetown University Medical Center)

  • Christopher Albanese

    (Georgetown University Medical Center)

  • Mohit Kapoor

    (University Health Network and University of Toronto)

  • Elena B. Pasquale

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Sana D. Karam

    (University of Colorado Denver)

Abstract

Differential outcomes of EphB4-ephrinB2 signaling offers formidable challenge for the development of cancer therapeutics. Here, we interrogate the effects of targeting EphB4 and ephrinB2 in head and neck squamous cell carcinoma (HNSCC) and within its microenvironment using genetically engineered mice, recombinant constructs, pharmacologic agonists and antagonists. We observe that manipulating the EphB4 intracellular domain on cancer cells accelerates tumor growth and angiogenesis. EphB4 cancer cell loss also triggers compensatory upregulation of EphA4 and T regulatory cells (Tregs) influx and their targeting results in reversal of accelerated tumor growth mediated by EphB4 knockdown. EphrinB2 knockout on cancer cells and vasculature, on the other hand, results in maximal tumor reduction and vascular normalization. We report that EphB4 agonism provides no additional anti-tumoral benefit in the absence of ephrinB2. These results identify ephrinB2 as a tumor promoter and its receptor, EphB4, as a tumor suppressor in HNSCC, presenting opportunities for rational drug design.

Suggested Citation

  • Shilpa Bhatia & Diemmy Nguyen & Laurel B. Darragh & Benjamin Van Court & Jaspreet Sharma & Michael W. Knitz & Miles Piper & Sanjana Bukkapatnam & Jacob Gadwa & Thomas E. Bickett & Shiv Bhuvane & Sophi, 2022. "EphB4 and ephrinB2 act in opposition in the head and neck tumor microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31124-7
    DOI: 10.1038/s41467-022-31124-7
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    References listed on IDEAS

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