The CAFs-derived YAP1-periostin axis forms a fibrotic tumor microenvironment to promote metastatic lung tumor growth

Abstract

The primary cause of poor prognosis in non-small cell lung cancer (NSCLC) patients is metastasis; however, little is known about the underlying mechanisms mediated by cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME). We conducted comprehensive molecular and cellular analyses, including RNA sequencing, immunohistochemistry, coculture experiments, and genetic mouse models, to investigate the role of the CD248-periostin-integrin β1 (ITGB1) axis in NSCLC metastasis. We demonstrated that CD248+ CAFs are key regulators of NSCLC metastasis. RNA sequencing and clinical sample analysis revealed that CD248 expression in CAFs was positively correlated with increased secretion of periostin (encoded by POSTN). In CAFs, elevated periostin expression is strongly linked to lymph node metastasis (p = 0.002), advanced tumor stage (p = 0.0039), and poor overall survival (p < 0.05) in patients with NSCLC. By promoting the nuclear translocation of YAP1 and regulating POSTN promoter activity to increase periostin expression, CD248 mechanistically causes YAP1 activation in CAFs. According to functional tests, CAFs secreted periostin binds to ITGB1 in NSCLC cells, triggering the FAK/Src signaling pathway to cause epithelial-mesenchymal transition (EMT)-like phenotypic changes and promote NSCLC cell invasion and migration. Additionally, periostin promotes collagen I deposition and increases extracellular matrix (ECM) stiffness, which further amplifies YAP1-driven periostin secretion from CD248+ CAFs, resulting in the formation of a prometastatic positive feedback loop. Fibroblast-specific CD248 deletion or POSTN knockout mice exhibit dramatically reduced metastatic tumor growth in NSCLC in vivo. This is accompanied by decreased ECM stiffness in the TME, decreased EMT-like phenotypic changes, and decreased collagen I deposition. Our results collectively suggested a CD248–YAP1-Periostin-ITGB1 axis that contributes to a prometastatic feedback loop in NSCLC, indicating that focusing on this axis may be a viable therapeutic approach to prevent NSCLC metastasis.