Researchers have identified a distinct tumor cell state in lung adenocarcinoma that is marked by the protein SCGB3A2 and characterized by low levels of angiogenesis. The finding, published in Experimental Hematology & Oncology, links this cell state to an extracellular signal involving PGK2 and angiostatin, offering a possible explanation for why some lung tumors resist vascularization.
Lung adenocarcinoma shows considerable diversity in how it drives angiogenesis and in how the tumor environment responds to anti-VEGF therapy. However, the tumor-cell-intrinsic mechanisms that prevent vascularization have remained poorly understood. SCGB3A2, also known as secretoglobin 3A2 or HIN-2/UGRP1, is a club and secretory cell marker found in pulmonary adenocarcinoma, but it had no established angiogenic function before this study.
The team used an unsupervised integration approach on two public lung adenocarcinoma single-cell RNA-seq cohorts to characterize the SCGB3A2-high malignant epithelial state. This state displayed an angiogenesis-low phenotype, indicated by low presence of VEGFA, hypoxic conditions, and low epithelial-mesenchymal transition, alongside a secretory and anti-inflammatory program.
To confirm these observations, the researchers examined independent bulk cohorts, including TCGA-LUAD and GSE72094. Tumors with high SCGB3A2 expression showed lower instances of angiogenesis, hypoxia, and scores related to epithelial-mesenchymal transition and invasion, consistent with the single-cell findings.
Spatial transcriptomics allowed the team to position SCGB3A2-high tumor cells next to endothelial cells and to identify a spatially inferred VEGFA/B–FLT1 interaction pattern, suggesting a specific molecular dialogue between these tumor cells and the vascular compartment.
In laboratory experiments with A549 and NCI-H1975 lung cancer cells, conditioned medium from SCGB3A2-overexpressing cells contained higher levels of extracellular PGK2-immunoreactive signal and angiostatin. This medium was associated with reduced HUVEC tube formation and reduced VEGFR2 phosphorylation, indicating diminished endothelial cell activation.
The authors conclude that SCGB3A2 serves as a marker for lung adenocarcinoma tumors characterized by low levels of angiogenesis, a property associated with an extracellular PGK2 and angiostatin signal.
Subject of Research: A SCGB3A2-marked low-angiogenesis tumor cell state in lung adenocarcinoma linked to extracellular PGK2 and angiostatin.
Article Title: SCGB3A2 marks a low-angiogenesis tumor cell state associated with extracellular PGK2 and angiostatin in lung adenocarcinoma
Article References: Zhao, S.-L., Cao, Y., Shi, Y.-Z., Zhang, M., Dai, F.-Q., Wang, T.-H., Liang, W., & Zhang, H. (2026). SCGB3A2 marks a low-angiogenesis tumor cell state associated with extracellular PGK2 and angiostatin in lung adenocarcinoma. Experimental Hematology & Oncology, 15(1), Article 117. https://doi.org/10.1186/s40164-026-00844-7
Image Credits: AI Generated
DOI: 10.1186/s40164-026-00844-7
Keywords: lung adenocarcinoma, SCGB3A2, angiogenesis, PGK2, angiostatin, single-cell RNA-seq, spatial transcriptomics, VEGFA, tumor microenvironment, anti-VEGF therapy, marks, low-angiogenesis
News Source: Nathaniel Bowman. (November 5, 2026). Tumor Cell State Linked to Low Angiogenesis Identified in Lung Adenocarcinoma. Scienmag.
