MUC1 promotes NSCLC progression by regulating ICAM-1-mediated mitochondria transfer from tCAFs to cancer cells.

Cancer-associated fibroblasts (tCAFs) promote non-small cell lung cancer (NSCLC) progression through cargo exchange with cancer cells. Mucin 1 (MUC1) initiates actin-mediated cytoskeleton protrusion movement to promote mitochondrial transfer. In this study, we aimed to investigate whether MUC1 regulates mitochondrial transfer from tCAFs to NSCLC cells. The results showed that lung cancer patients with high MUC1 expression had a poor prognosis, and MUC1 protein was significantly enriched in exosomes (EXOs) derived from tCAFs. A549 cells were treated with conditioned medium (CM) or EXOs derived from tCAFs or co-cultured with tCAFs in contact or non-contact ways. Both CM and EXOs promoted the proliferation and invasion and inhibited apoptosis in A549 cells, while MUC1-interfered EXOs inhibited A549 cell proliferation and invasion and induced apoptosis. Meanwhile, non-contact co-culture of tCAFs and A549 cells promoted proliferation, invasion, and colony formation of A549 cells, and contact co-culture further promoted malignant phenotype of A549 cells and enhanced mitochondrial function in A549 cells. Mechanism studies revealed that MUC1 promotes mitochondrial transfer from tCAFs to A549 cells by interacting with intercellular adhesion molecule-1 (ICAM1), promoting malignant phenotype of A549 cells. ICAM1 interference counteracted the effect of EXO protein MUC1 on A549 cells. Finally, lung cancer xenograft tumor models were constructed and found that EXO protein MUC1 promoted lung cancer tumor growth in vivo, while ICAM1 interference inhibited tumor growth. In conclusion, MUC1 is enriched in EXOs derived from tCAFs and promotes NSCLC progression by regulating ICAM1-mediated mitochondria transfer from tCAFs to cancer cells.