Spatial and single-cell transcriptomic profiling reveals interplay between SRGN-associated epithelial programs and C1QC+ macrophages in early LUAD progression

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. 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. 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. 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.