Spatial and single-cell transcriptomic profiling reveals interplay between SRGN-associated epithelial programs and
Shengqiang Mao1, Chunwei Pang2, Hong Hang1
1Department of Respiratory and Critical Care Medicine, Frontiers Science Center for Disease-Related Molecular Network, Center of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
Background:
Deciphering the molecular and cellular mechanisms underlying the progression of early-stage lung adenocarcinoma (LUAD) is critical for advancing early detection and therapeutic strategies. This study aims to map the evolutionary trajectory from precursor lesions to invasive adenocarcinoma.
Methods:
We integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomic analyses to evaluate LUAD progression across four histologic stages:atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC). Findings were further validated using a stage-specific A/J mouse model to confirm functional cellular interactions.
Results:
We identified a tumor-intrinsic program characterized by elevated SRGN expression that is associated with Epithelial-Mesenchymal Transition (EMT) and cell proliferation, intensifying as the disease progresses. In parallel, a stage-dependent accumulation of C1QC+ macrophages was observed. Spatial colocalization analysis revealed that SRGN+ malignant cells and C1QC+ macrophages are closely positioned within the tumor microenvironment. We detected progressively enhanced interactions between SRGN+ malignant cells and both exhausted T cells and C1QC+ macrophages, mediated by specific receptor-ligand pairs, including MIF-LIFR, ADAM17-ERBB4, OSM-EGFR, and OSM-TNFRSF14. The A/J mouse models confirmed the co-emergence and functional cooperation of these populations.
Conclusions:
Our findings highlight a coordinated epithelial-macrophage module that drives LUAD progression. The identification of SRGN and its associated spatial interactions offers potential molecular targets for early therapeutic intervention and diagnostic modeling.
