Exploring the mechanism of AGR2 regulating the progression of pancreatic ductal adenocarcinoma and remodeling of the tumor microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive and lethal malignant tumor characterized by extensive desmoplasia. We found that AGR2 deletion reshapes the tumor microenvironment by affecting the activation of the IGF1 signaling pathway. On the one hand, AGR2, as an endoplasmic reticulum protein, promoted correct folding and cell surface distribution of IGF1R. On the other hand, AGR2 was secreted into the extracellular space, promoting IGF1 transcription by activating the WNT pathway in cancer-associated fibroblasts (CAFs). Through these mechanisms, AGR2 significantly enhanced the IGF1 signal in the PDAC tumor microenvironment, accelerating the formation of desmoplasia and an immunosuppressive microenvironment. Overall design: In order to investigate the effect of AGR2 on pancreatic ductal adenocarcinoma (PDAC) tumor cells, we knocked out AGR2 in panc1 and capan2 cells using CRISPR/Cas9 technology and selected monoclonal cell lines. We performed RNA sequencing on the above-mentioned cell lines after AGR2 knockout. To investigate the effect of secreted AGR2 on cancer-associated fibroblasts (CAFs), we subjected CAFs derived from human PDAC to 12 hours of serum starvation followed by treatment with rAGR, TGFß, and IL1a for 24 hours.