Exosomal POSTN from cancer-associated fibroblasts drives progression of microinvasive lung adenocarcinoma: insights from single-cell and tissue exosome sequencing analysis.

BACKGROUND

Microinvasive adenocarcinoma (MIA) represents an early stage of lung adenocarcinoma (LUAD), yet how the tumor microenvironment (TME) and cancer-associated fibroblast (CAF)-derived exosomes contribute to its progression remains unclear. We aimed to define the cellular ecosystem of MIA and to clarify the role of periostin (POSTN) and POSTN+ CAF-derived exosomes in early LUAD progression.

METHODS

Single-cell RNA sequencing (scRNA-seq) and tissue-derived exosomal RNA sequencing were performed on four primary MIA lesions and matched adjacent lung tissues. Integrated analyses of scRNA-seq data, exosomal transcriptomes, the TCGA-LUAD cohort, and an independent LUAD tissue/serum cohort were used to characterize POSTN expression and to evaluate its prognostic and diagnostic relevance. Primary MIA-associated POSTN+ and POSTN- CAFs were isolated for exosome preparation, followed by co-culture experiments with LUAD cell lines and xenograft assays.

RESULTS

scRNA-seq identified a malignant Cancer-alveolar type II (Cancer-AT2) epithelial subset and multiple CAF subsets. Among these, POSTN+ CAFs were enriched in MIA tissues and showed enhanced crosstalk with Cancer-AT2 cells through extracellular matrix (ECM)-related ligand-receptor interactions. Tissue-derived exosomes contained 588 differentially expressed mRNAs, among which POSTN was markedly upregulated and showed the strongest association with fibroblast-related signatures. POSTN was predominantly expressed in fibroblasts across independent non-small cell lung cancer datasets and was elevated in LUAD tissues, tissue-derived exosomes, and serum exosomes, correlating with advanced stage, lymph node metastasis, and poor survival. Functionally, POSTN+ CAF-derived exosomes promoted LUAD cell proliferation, migration, invasion, colony formation, and xenograft growth.

CONCLUSION

Exosomal POSTN derived from POSTN+ CAFs may represent an important stromal mediator of MIA/LUAD progression and a potential diagnostic and prognostic biomarker in early-stage LUAD.