PLVAP mediates the regulation of the tumour microenvironment in early-stage lung adenocarcinoma

Abstract

Background: Early tumour vascular invasion contributes to cancer progression. Tip cells, a subset of tumour endothelial cells, significantly decline after anti-angiogenic therapy. However, their behaviour and the roles of their signature genes during early invasion are incompletely understood.

Methods: This study employed single-cell transcriptomic analysis and 10x Genomics Visium spatial transcriptomics on fresh lung tissues from patients with pulmonary nodules and from Kras^G12D (K) and Kras^G12DTgfbr2^−/− (KT) mice. The role of plasma vesicle-associated protein (PLVAP), a tip cell marker, was further examined using survival databases, immunofluorescence, in vitro co-culture, cell migration, invasion assays and endothelial tube formation.

Results: Tip cell proportions were elevated in early-stage lung adenocarcinoma (LUAD) tissues and KT mice, with evidence suggesting they arise from capillaries type I. PLVAP expression was enriched in tumour endothelial cells, induced by TGFβ1, and negatively correlated with patient prognosis. Functionally, PLVAP promoted endothelial cell invasion, migration and angiogenesis, and regulated tumour cell invasiveness. Intercellular analysis revealed that some tip cells also expressed TGFβ1, which may act on adjacent tumour cells to enhance invasion during early tumour development.

Conclusion: Tip cells increased during early LUAD progression and likely evolved from capillaries type I. Their marker PLVAP was associated with poor prognosis and pro-invasive endothelial behaviour. Tumour-secreted TGFβ1 upregulated PLVAP in endothelial cells, promoting angiogenesis and tumour invasion. Additionally, tip-cell-derived TGFβ1 may further stimulate tumour aggressiveness, highlighting a reciprocal interaction that contributes to early tumour progression.

Keywords

PLVAP / single-cell RNA sequencing / tip cells / tumour endothelial cells

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.