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Background <p>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.</p> Methods <p>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.</p> Results <p>We identified a tumor-intrinsic program characterized by elevated <i>SRGN</i> 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 <i>MIF</i>–<i>LIFR</i>, <i>ADAM17</i>–<i>ERBB4</i>, <i>OSM</i>–<i>EGFR</i>, and <i>OSM</i>–<i>TNFRSF14</i>. The A/J mouse models confirmed the co-emergence and functional cooperation of these populations.</p> Conclusions <p>Our findings highlight a coordinated epithelial-macrophage module that drives LUAD progression. The identification of <i>SRGN</i> and its associated spatial interactions offers potential molecular targets for early therapeutic intervention and diagnostic modeling.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月23日

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  • Shengqiang Mao,
  • Chunwei Pang,
  • Hong Hang,
  • Yalun Li,
  • Li Zhang

摘要

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.