Single-cell profiling uncovers the intricate pathological niche diversity in brain, lymph node, bone, and adrenal metastases of lung cancer.

PURPOSE

The aim of this study is to explore the pathological niche of cancer metastasis and the site-specific interactions between tumor cells and the microenvironment, understand the mechanisms driving metastasis progression and identify potential therapeutic targets.

METHODS

Data from four lung cancer metastasis datasets (GSE123902, GSE131907, GSE148071, and GSE186344) were downloaded and subjected to stringent quality control and filtering. Cell types were identified using canonical markers, and pseudotime trajectory analysis was performed to evaluate cell differentiation. Functional and pathway enrichment analyses, including ssGSEA and GO/KEGG, were conducted. CellphoneDB was used to analyze intercellular communication, ranking receptor-ligand interactions based on communication strength.

RESULTS

Eleven cell types were identified after quality control, revealing significant heterogeneity and site-specific functionality in lung cancer metastases. CTLs showed notable activity in antigen presentation and T-cell differentiation pathways, with DNAJB1⁺ CTLs playing a dominant role in cytotoxicity and immune regulation. B cells, myeloid cells, and CAFs were involved in immune modulation, defense, and matrix remodeling through specific signaling pathways. Tumor cell subclusters drove proliferation, migration, and immune evasion via immune-regulatory, Hippo, and TGF-beta pathways. No overlapping pathways were observed across metastatic sites. Cell communication analysis identified PPIA-BSG and APP-CD74 as key axes in brain and lymph node metastases, while FN1-Integrin and CTLA4-CD86 dominated in bone and adrenal metastases, respectively.

CONCLUSIONS

In summary, this study highlights the functional heterogeneity and site-specific interactions of cells in lung cancer metastases, providing insights into the mechanisms shaping metastatic niches and potential therapeutic strategies.