CD105+CAF-derived exosomes CircAMPK1 promotes pancreatic cancer progression by activating autophagy.

Previous studies have shown that the heterogeneity of tumor-associated fibroblasts (CAFs) in the tumor microenvironment may play a critical role in tumorigenesis; however, the biological function of CAFs in pancreatic cancer is still controversial. In this study, we found that CD105-positive (CD105⁺) CAF-derived exosomes significantly promoted the proliferative and invasive metastatic abilities of pancreatic cancer cells. Furthermore, RNA-seq and qRT‒PCR experiments revealed circAMPK1 as a key molecule in exosomes from CD105⁺ CAFs that mediates the malignant progression of pancreatic cancer. Furthermore, we demonstrated that circAMPK1 encodes a novel protein (AMPK1-360aa) in pancreatic cancer cells. This protein competes with AMPK1 to bind to the ubiquitination ligase NEDD4, which inhibits AMPK1 protein degradation and ubiquitination and thereby increases AMPK1 levels. Finally, we demonstrated that AMPK1-360aa induces cellular autophagy via NEDD4/AMPK1 to promote the proliferation and invasion of pancreatic cancer cells. In summary, circAMPK1 in CD105⁺ CAF-derived exosomes may mediate pancreatic cancer cell proliferation and invasive metastasis by inducing autophagy in target cells. Moreover, circAMPK1 may competitively bind to ubiquitinating enzymes through the encoded protein AMPK1-360aa, which in turn inhibits the ubiquitination-mediated degradation of AMPK1 and contributes to the upregulation of AMPK1 expression, thus inducing cellular autophagy to mediate the malignant progression of pancreatic cancer.