Manipulating the EphB4-ephrinB2 axis to reduce metastasis in HNSCC

Khalid N M Abdelazeem; Diemmy Nguyen; Sophia Corbo; Laurel B Darragh; Mike W Matsumoto; Benjamin Van Court; Brooke Neupert; Justin Yu; Nicholas A Olimpo; Douglas Grant Osborne; Jacob Gadwa; Richard B Ross; Alexander Nguyen; Shilpa Bhatia; Mohit Kapoor; Rachel S Friedman; Jordan Jacobelli; Anthony J Saviola; Michael W Knitz; Elena B Pasquale; Sana D Karam

doi:10.1038/s41388-024-03208-9

Manipulating the EphB4-ephrinB2 axis to reduce metastasis in HNSCC

Oncogene. 2024 Nov 3. doi: 10.1038/s41388-024-03208-9. Online ahead of print.

Authors

Khalid N M Abdelazeem^#^{1

2}, Diemmy Nguyen^#¹, Sophia Corbo¹, Laurel B Darragh^{1

3}, Mike W Matsumoto⁴, Benjamin Van Court¹, Brooke Neupert¹, Justin Yu⁵, Nicholas A Olimpo¹, Douglas Grant Osborne⁶, Jacob Gadwa^{1

3}, Richard B Ross¹, Alexander Nguyen¹, Shilpa Bhatia¹, Mohit Kapoor⁷, Rachel S Friedman^{3

8}, Jordan Jacobelli^{3

8}, Anthony J Saviola⁹, Michael W Knitz¹, Elena B Pasquale⁴, Sana D Karam^{10

11}

Affiliations

¹ Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
² Radiation Biology Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt.
³ Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴ Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
⁵ Department of Otolaryngology - Head and Neck Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁶ Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁷ Krembil Research Institute, University Health Network, and University of Toronto, Toronto, ON, Canada.
⁸ Barbara Davis Research Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁹ Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Center, Aurora, CO, USA.
¹⁰ Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. [email protected].
¹¹ Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA. [email protected].

^# Contributed equally.

PMID: 39489818
DOI: 10.1038/s41388-024-03208-9

Abstract

The EphB4-ephrinB2 signaling axis has been heavily implicated in metastasis across numerous cancer types. Our emerging understanding of the dichotomous roles that EphB4 and ephrinB2 play in head and neck squamous cell carcinoma (HNSCC) poses a significant challenge to rational drug design. We find that EphB4 knockdown in cancer cells enhances metastasis in preclinical HNSCC models by augmenting immunosuppressive cells like T regulatory cells (Tregs) within the tumor microenvironment. EphB4 inhibition in cancer cells also amplifies their ability to metastasize through increased expression of genes associated with hallmark pathways of metastasis along with classical and non-classical epithelial-mesenchymal transition. In contrast, vascular ephrinB2 knockout coupled with radiation therapy (RT) enhances anti-tumor immunity, reduces Treg accumulation into the tumor, and decreases metastasis. Notably, targeting the EphB4-ephrinB2 signaling axis with the engineered ligands ephrinB2-Fc-His and Fc-TNYL-RAW-GS reduces local tumor growth and distant metastasis in a preclinical model of HNSCC. Our data suggests that targeted inhibition of vascular ephrinB2 while avoiding inhibition of EphB4 in cancer cells could be a promising strategy to mitigate HNSCC metastasis.

Abstract

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