Exploring the mechanism of AGR2 regulating the progression of pancreatic ductal adenocarcinoma and remodeling of the tumor microenvironment [CUT&Tag]

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. In order to investigate the transcriptional regulation of AGR2 by c-JUN, Panc1 cells were subjected to Cleavage Under Targets and Tagmentation (CUT&Tag) assays using c-JUN antibody after 12 hours of serum starvation with or without IGF1 treatment.