VANGL1 links angiogenesis-stemness programs and tumor microenvironment remodeling: a pan-cancer, multi-omics study
Wei Zhou1,2,3, Lizhen Wang4,5, Mengxing Li6
1Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China.
Background:
The tumor microenvironment (TME) critically determines cancer progression, yet master regulators orchestrating microenvironmental remodeling across malignancies remain elusive. VANGL1, a core planar cell polarity component, has been implicated in tissue morphogenesis, but its pan-cancer landscape and TME regulatory mechanisms are unexplored.
Methods:
We conducted comprehensive pan-cancer analysis of VANGL1 across 33 tumor types using bulk transcriptomic, single-cell RNA sequencing, and spatial transcriptomic datasets. Intercellular communication was dissected using CellChat. Functional mechanisms were investigated through PPI networks, CancerSEA, and GSEA. Experimental validation employed loss-of-function studies in PC9, HCT116, and Bel7402 cells, patient-derived tumor organoids, and hepatocellular carcinoma stem cell-derived xenografts.
Results:
VANGL1 was significantly upregulated across solid tumors and as-sociated with poor prognosis. Single-cell analysis revealed VANGL1+ malignant cells exhibited enhanced communication with fibroblasts, endothelial cells, and immune cells through MIF, VEGF, and ANGPTL pathways. Mechanistically, VANGL1 integrated Wnt/Notch/mTOR signaling with cancer stemness and angiogenesis. VANGL1 knock-down suppressed proliferation, migration, and invasion in vitro, and attenuated tumor growth, angiogenesis, and cancer stem cell maintenance in vivo.
Conclusions:
Our study identifies VANGL1 as a pan-cancer master regulator integrating cancer stemness, angio-genesis, and microenvironmental remodeling, establishing therapeutic rationale for targeting the VANGL1-driven TME niche.
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