MSC C1: A Potential Hub Linking Stromal Plasticity, Immune Regulation, and Patient Survival in Lung Adenocarcinoma

Bone metastasis of lung adenocarcinoma (LUAD) directly leads to poor prognosis. This study aimed to dissect the stromal landscape of LUAD with bone metastases. Unsupervised clustering of scRNA-seq data from LUAD patients with bone metastasis identifies stromal subsets. Pseudotime analysis combined with CytoTRACE stemness scoring reconstructs mesenchymal stromal cell (MSC) differentiation trajectories, while CellChat characterizes cell-cell communication networks among MSC subpopulations. Differentially expressed genes (DEGs) specific to functionally distinct MSC subsets are subjected to LASSO-Cox regression for construction of a prognostic RiskScore model, which is validated in independent bulk RNA-seq cohorts regarding overall survival, immune cell infiltration, and drug sensitivity. A distinct high-stemness MSC C1 subpopulation is localized at the bifurcation point of two divergent differentiation trajectories toward a matrix-remodeling fate and a secretory, immunomodulatory phenotype. The RiskScore model stratifies patients into low- and high-risk groups with divergent overall-survival outcomes. Reduced infiltration of cytotoxic lymphocytes is observed in high-risk patients, and higher drug sensitivity within the high-risk subgroup. In vitro assays verify that LDHA knockdown impairs proliferation and migration in A549 cells. This study provides a rationale for targeting stroma-derived genes in risk-adapted therapy.