Fig. 9. Schematic model showing the essential role of AGO2 in PDAC progression.
Expression of KRASG12D in normal pancreatic cells initiates low grade PanINs which progress to higher grade PanINs, PDAC, and metastases. PanIN formation requires EGFR that can phosphorylate AGO2 to disrupt the KRAS-AGO2 interaction and is, therefore, AGO2-independent. PDAC progression is associated with increased expression of KRAS and AGO2 at the membrane. AGO2 ablation results in increased expression of microRNAs that regulate cell proliferation and senescence and also activates KRAS to promote oncogene-induced senescence. OIS due to AGO2 loss prevents progression of low grade PanINs to PDAC and leads to infiltration by natural killer (NK) cells.