Reprogramming of fibroblasts into cancer-associated fibroblasts via IGF2-mediated autophagy promotes metastasis of lung cancer cells

Cancer-associated fibroblasts (CAFs) are major component of stromal cells. Growing evidence suggests that CAFs promote tumor growth and metastasis; however, the reprogramming of normal fibroblasts (NFs) into CAFs by tumor cells still remains largely unknown. In this study, we found that non-small cell lung cancer (NSCLC) cells activated NFs into CAFs via autophagy induction. Insulin-like growth factor 2 (IGF2) secreted by NSCLC cells mediated NSCLC cells’ effect on autophagy induction and CAFs activation. Importantly, the activated CAFs promoted NSCLC cells growth, migration, and invasion. Further study showed that the activated CAFs facilitated NSCLC cells invasion via promoting epithelial-mesenchymal transition (EMT) process, upregulating metastasis-related genes, releasing CXCL12, and activating its downstream AKT serine/threonine kinase 1 (AKT)/ nuclear factor κB (NF-κB) signaling pathway. These findings revealed that IGF2-mediated autophagy plays a critical role in CAFs activation and suggested the IGF2-autophagy cascade in fibroblasts could be a potential target for lung cancer therapy.