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

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, Sophia Corbo, Brian Wu, Yichien Lee, Mayumi Fujita, Molishree Joshi, Lynn E. Heasley, Robert L. Ferris, Olga Rodriguez, Christopher Albanese, Mohit Kapoor, Elena B. Pasquale and Sana D. Karam ()
Additional contact information
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
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

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31124-7

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DOI: 10.1038/s41467-022-31124-7

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