Abdelazeem Khalid N M, Nguyen Diemmy, Corbo Sophia, Darragh Laurel B, Matsumoto Mike W, Van Court Benjamin, Neupert Brooke, Yu Justin, Olimpo Nicholas A, Osborne Douglas Grant, Gadwa Jacob, Ross Richard B, Nguyen Alexander, Bhatia Shilpa, Kapoor Mohit, Friedman Rachel S, Jacobelli Jordan, Saviola Anthony J, Knitz Michael W, Pasquale Elena B, Karam Sana D
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.
Oncogene. 2025 Feb;44(3):130-146. doi: 10.1038/s41388-024-03208-9. Epub 2024 Nov 3.
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.
EphB4-ephrinB2信号轴在多种癌症类型的转移中起着重要作用。我们对EphB4和ephrinB2在头颈部鳞状细胞癌（HNSCC）中所起的双重作用的新认识，对合理的药物设计构成了重大挑战。我们发现，在临床前HNSCC模型中，癌细胞中EphB4的敲低通过增加肿瘤微环境中免疫抑制细胞（如调节性T细胞（Tregs））来增强转移。癌细胞中EphB4的抑制还通过增加与转移标志性途径以及经典和非经典上皮-间质转化相关基因的表达，放大了它们的转移能力。相比之下，血管内皮ephrinB2基因敲除联合放射治疗（RT）可增强抗肿瘤免疫力，减少Tregs在肿瘤中的积累，并减少转移。值得注意的是，在HNSCC临床前模型中，用工程化配体ephrinB2-Fc-His和Fc-TNYL-RAW-GS靶向EphB4-ephrinB2信号轴可减少局部肿瘤生长和远处转移。我们的数据表明，在避免抑制癌细胞中EphB4的同时，靶向抑制血管内皮ephrinB2可能是减轻HNSCC转移的一种有前景的策略。
