Manipulating the EphB4-ephrinB2 axis to reduce metastasis in HNSCC
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.
Authors
- Khalid N.M. Abdelazeem (ORCID: https://orcid.org/0000-0002-0672-7900)
- Michael W. Knitz (ORCID: https://orcid.org/0000-0002-5786-9837)
- Alexander Nguyen (ORCID: https://orcid.org/0009-0004-1108-2176)
- Elena B. Pasquale (ORCID: https://orcid.org/0000-0002-5076-4848)
- Laurel B. Darragh (ORCID: https://orcid.org/0000-0002-6445-7988)
- Sana D. Karam (ORCID: https://orcid.org/0000-0003-1676-5967)
- Brooke Neupert
- Rachel S. Friedman (ORCID: https://orcid.org/0000-0001-7549-6387)
- Shilpa Bhatia
- Nicholas A. Olimpo (ORCID: https://orcid.org/0000-0001-6556-2168)
- Mike W. Matsumoto (ORCID: https://orcid.org/0009-0001-0618-7799)
- Justin Yu (ORCID: https://orcid.org/0000-0001-5917-5401)
- Diemmy Nguyen (ORCID: https://orcid.org/0000-0002-2035-643X)
- Jacob Gadwa (ORCID: https://orcid.org/0000-0003-0560-2337)
- Mohit Kapoor (ORCID: https://orcid.org/0000-0001-7994-110X)
- Richard B. Ross (ORCID: https://orcid.org/0000-0002-9279-9168)
- Jordan Jacobelli (ORCID: https://orcid.org/0000-0001-6612-6704)
- Anthony J. Saviola (ORCID: https://orcid.org/0000-0001-6890-512X)
- Sophia Corbo (ORCID: https://orcid.org/0000-0002-1179-6425)
- Douglas G. Osborne (ORCID: https://orcid.org/0000-0002-6772-7031)
- Benjamin Van Court (ORCID: https://orcid.org/0000-0001-5860-4489)
Institutions
- University Health Network (CA)
- University of Toronto (CA)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Washington University in St. Louis (US)
- Discovery Institute (US)
- Egyptian Atomic Energy Authority (EG)
- Krembil Research Institute
- University of Colorado Anschutz Medical Campus (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Oncogene
- Published
- 2024-11-03
- DOI
- https://doi.org/10.1038/s41388-024-03208-9
- Citations
- 4
- Primary Topic
- Axon Guidance and Neuronal Signaling
- Type
- article
- Field-Weighted Citation Impact
- 1.07
Funders
- V Foundation for Cancer Research
- National Institutes of Health
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases