Manipulating the EphB4-ephrinB2 axis to reduce metastasis in HNSCC.

Autor:	Abdelazeem KNM; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.; Radiation Biology Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt., Nguyen D; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Corbo S; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Darragh LB; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Matsumoto MW; Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Court BV; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Neupert B; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Yu J; Department of Otolaryngology - Head and Neck Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Olimpo NA; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Osborne DG; Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Gadwa J; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Ross RB; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Nguyen A; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Bhatia S; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Kapoor M; Krembil Research Institute, University Health Network, and University of Toronto, Toronto, Ontario, Canada., Friedman RS; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Barbara Davis Research Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Jacobelli J; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Barbara Davis Research Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Saviola AJ; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Center, Aurora, CO, USA., Knitz MW; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA., Pasquale EB; Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Karam SD; Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jul 23. Date of Electronic Publication: 2024 Jul 23.
DOI:	10.1101/2024.07.21.604518
Abstrakt:	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 epithelial mesenchymal transition and hallmark pathways of metastasis. 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 EphB4 ligands EFNB2-Fc-His and Fc-TNYL-RAW-GS reduces local tumor growth and distant metastasis in a preclinical model of HNSCC. Our data suggest that targeted inhibition of vascular ephrinB2 while avoiding inhibition of EphB4 in cancer cells could be a promising strategy to mitigate HNSCC metastasis. Competing Interests: Dr. Karam receives clinical funding from Genentech that does not relate to this work. She receives clinical trial funding from AstraZeneca, a part of which is included in this manuscript. She also receives preclinical research funding from Roche and Amgen, neither one of which is related to this manuscript. The remaining authors declare no competing interests.
Databáze:	MEDLINE
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