Abstract
Most advanced lung adenocarcinoma (LUAD) patient deaths are attributed to metastasis. However, the complete understanding of the metastatic mechanism in LUAD remains elusive. Single-cell RNA-seq (scRNA-seq), spatial RNA-seq (stRNA-seq) and bulk RNA-seq of primary LUAD were integrated to investigate metastatic driver genes, cell-cell interactions, and spatial colocalization of cells and ligand-receptor pairs. A lung adenocarcinoma metastasis risk scoring model (LMRS) was established to estimate the risk of metastasis in LUAD. Forty-two metastasis driver genes were identified and tumor epithelial cells were classified into two subtypes. Epithelial cell subclass characterized by susceptibility to metastasis are referred to as Epithelial_LM, and the remaining as Epithelial_LL. Epithelial_LM subtype has intimate ligand-receptor interactions with inflammatory endothelial cells (iendo), inflammatory cancer-associated fibroblasts (iCAF), and NKT cells. Epithelial_LM cells have a spatial colocalization relationship with these three types of cells. The LMRS was established and its efficacy was verified in bulk RNA-seq. We identified a subclass of epithelial cells prone to metastasis and demonstrated the contribution of inflammatory stromal cells and NKT cells in facilitating tumor metastasis.