Spatial Location of SPP1 + TAMs and Mutually Exclusive Subsets Based on Single‐Cell and Transcriptome Data

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ABSTRACT To clarify locations and mutually exclusive subsets of SPP1 + tumor associated macrophages (SPP1 + TAMs) in lung adenocarcinoma (LUAD). Analyze the polarization type, mutually exclusive cell subset, and spatial location of SPP1 + TAMs based on the transcriptome data of the Cancer Genome Atlas (TCGA) and Genotype‐Tissue Expression (GTEx) database, single‐cell and spatial transcriptome data of the Gene Expression Omnibus database (GEO), immunohistochemical data of the Human Protein Atlas (HPA) database and local LUAD to provide a scientific basis for precision treatment of LUAD. Secreted phosphoprotein‐1 (SPP1) was identified as the central regulatory gene of LUAD. The single‐cell transcriptome data showed that SPP1 is up‐regulated in invasive lung carcinoma (ILC), while macrophage receptor with collagenous structure (MARCO) is up‐regulated in adenocarcinoma in situ (AIS). MARCO + M2 macrophages and SPP1 + M2 macrophages clustered in different positions in the uniform manifold approximation and projection (UMAP) to form mutually exclusive cell subsets. SPP1 + M2 plays a major role in ILC and MARCO + M2 plays a major role in AIS. The spatial transcriptome data showed that some SPP1 + M2 were clustered at the edge of the tumor, and this particular spatial location may increase tumor invasiveness. Further spatial distance analysis showed that the distance was greater from the SPP1 + M2 to alveolar type 2 epithelial cell (AT2) than from the MARCO + M2. Immunohistochemical analysis showed that SPP1 expression was up‐regulated in the tumor or ILC group and notably higher in inflammatory cells. In summary, SPP1 + M2 and MARCO + M2 form mutually exclusive cell subsets, and MARCO + M2 and SPP1 + M2 synergistically promote different stages of tumor progression.

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