SCGB3A2 marks a low-angiogenesis tumor cell state associated with extracellular PGK2 and angiostatin in lung adenocarcinoma

LUAD exhibits diversity in the mechanisms of angiogenesis and the tumor environment’s responses to anti-VEGF therapy, while the tumor-cell-intrinsic mechanisms that prevent vascularization are not well understood. SCGB3A2 (secretoglobin 3A2; HIN-2/UGRP1) is a club/secretory marker of pulmonary adenocarcinoma without established angiogenic function. By using an unsupervised integration approach of two public LUAD single-cell RNA-seq cohorts, we described a SCGB3A2-high malignant epithelial state characterized by an angiogenesis-low phenotype as indicated by the low presence of VEGFA, hypoxic conditions, and a low epithelial-mesenchymal transition (EMT), along with a secretory/anti-inflammatory program, which was confirmed in independent bulk cohorts (TCGA-LUAD, GSE72094) showing that SCGB3A2-high tumors experienced lower instances of angiogenesis, hypoxia, and scores related to EMT/invasion. Using spatial transcriptomics, we positioned SCGB3A2-high tumor cells next to endothelial cells and identified a spatially inferred VEGFA/B–FLT1 interaction pattern. In A549 and NCI-H1975 cells, conditioned medium from SCGB3A2-overexpressing cells contained higher levels of extracellular PGK2-immunoreactive signal and angiostatin and was associated with reduced HUVEC tube formation and VEGFR2 phosphorylation. Thus, SCGB3A2 is a marker for LUAD tumors characterized by low levels of angiogenesis, which is associated with an extracellular PGK2/angiostatin signal.