Abstract Cutaneous squamous cell carcinoma (cSCC) represents a growing public health challenge, with 200,000 Americans diagnosed annually and limited therapeutic interventions. Despite widespread awareness of ultraviolet B (UVB) radiation as a primary etiologic factor, current prevention strategies remain inadequate, underscoring the urgent need for mechanism-based approaches to interrupt cSCC development and progression. Our investigation unveils a critical molecular mechanism by which CXCL17 drives pro-angiogenic signaling in human microvascular endothelial cells. Comprehensive molecular analysis revealed a profound activation of key oncogenic and angiogenic pathways upon CXCL17 treatment, with significant phosphorylation of endothelial nitric oxide synthase (eNOS), protein kinase B (pAKT), nuclear factor kappa B (NFκB), and hypoxia-inducible factor-1α (HIF-1α). The coordinated activation of these signaling molecules suggests a robust angiogenic reprogramming mechanism. Notably, eNOS phosphorylation indicates enhanced nitric oxide production, a critical mediator of endothelial proliferation and vessel formation. Concurrent AKT activation promotes endothelial cell survival, while NFκB and HIF-1α upregulation demonstrates metabolic and inflammatory adaptations that support aggressive vascular remodeling. Syngeneic Tumor-Cell Xenograft model corroborated these molecular findings, demonstrating significantly reduced CD31 staining in CXCL17-knockout tumors, directly linking CXCL17 to tumor angiogenesis. Clinical correlation studies further substantiated CXCL17's role in metastatic potential, with elevated expression associated with increased perineural invasion and tumor aggressiveness. Our comprehensive analysis establishes CXCL17 as a pivotal molecular orchestrator of angiogenic processes in cutaneous squamous cell carcinoma, offering novel insights into tumor progression mechanisms. Citation Format: Alok R. Khandelwal, Cherie-Ann O. Nathan, Keerthan Jaganmohan. CXCL17 Drives angiogenesis to promote progression in cutaneous squamous cell carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4796.
Khandelwal et al. (2026) studied this question.