Mechanisms and therapeutic targets in distant metastasis of lung adenocarcinoma.

Distant metastasis, characterized by organotropism, is a major cause of mortality in lung adenocarcinoma (LUAD). In this study, digital spatial profiling (DSP), multiplex immunofluorescence (mIF), and clinical data from 52 LUAD patients were integrated to develop organ-specific metastasis risk models, and the molecular mechanisms underlying metastatic organotropism were investigated. Random forest models based on primary tumor spatial transcriptomics accurately predicted metastasis to the brain (AUC = 0.974), liver (AUC = 0.975), adrenal gland (AUC = 0.929), and bone (AUC = 0.907). Key compartment-specific gene expression signatures associated with organotropic metastasis were identified, including those expressed in tumors (e.g., FKBP1A for the brain and MOCOS for the liver), immune cells (e.g., ADAMTSL2 for the liver), and stromal cells (e.g., CKAP2 for the brain). Pathway analyses revealed distinct biological processes associated with organotropism, such as enriched cell death pathways in brain metastasis and extracellular matrix (ECM) remodeling in liver metastasis. Postmetastasis survival models highlight stromal gene expression (e.g., PKM for OS and VCAM1 for PFS) and immunosuppressive microenvironments (e.g., M2 macrophage infiltration) as critical prognostic factors. The high-precision prediction models and key molecular signatures identified in this study enhance our understanding of "seed-soil" interaction dynamics and offer promising biomarkers and therapeutic targets for future clinical use.