Hypoxia-activated endothelial cells drive stemness and vasculogenic mimicry in NSCLC via a HIF-1α/ITPR3 axis.

Authors

Wenhao Ji, Shizhou Yang, Xiaojing Lai, Zhen Zhang, Ruting Wang, Weimin Mao

Published in

Biochemical pharmacology. Pages 118329. Aug 06, 2026. Epub Aug 06, 2026.

Abstract

Vasculogenic mimicry (VM) predicts poor prognosis in non-small cell lung cancer (NSCLC). Hypoxia is a critical tumor microenvironmental regulator, yet its detailed mechanism linking to VM formation remains poorly defined. This study aimed to elucidate the role of hypoxic endothelial cells in promoting NSCLC aggressiveness and VM formation. We integrated clinical data analysis, single-cell RNA sequencing (scRNA-seq), transcriptomic profiling, and multiple in vitro and in vivo functional validations to consolidate our findings. Clinical NSCLC data revealed a positive correlation between endothelial expression of the hypoxia marker carbonic anhydrase IX (CA9) and VM activity. Conditioned medium from hypoxic HUVECs promoted NSCLC cell proliferation, migration, invasion, stemness, and VM network formation in vitro. Endothelial HIF-1α overexpression accelerated tumor growth and VM in vivo. Transcriptomics screening pinpointed the calcium channel gene Inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) as the core downstream effector in this hypoxic endothelial paracrine signaling. Follow-up mechanistic assays revealed that hypoxic endothelial supernatant and the ITPR3 inhibitor 2-aminoethoxydiphenyl borate (2-APB) activated calcium/endoplasmic reticulum (ER) stress signaling to promote malignant phenotypes in NSCLC, and these effects were further validated by ITPR3 knockdown. In conclusion, hypoxia-activated endothelial cells drive NSCLC aggressiveness and VM through a paracrine axis involving ITPR3-mediated ER calcium activation. This HIF-1α/ITPR3 axis represents a potential therapeutic target for disrupting the tumor-vascular niche in NSCLC.

PMID:
42562338
Bibliographic data and abstract were imported from PubMed on 07 Aug 2026.

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