Genetic variants and gene expression profiles of the earliest PanIN lesions

Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutation. It is the earliest step of genetic alterations, but oncogenic KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. What factors are required for oncogenic KRAS-mutated pancreatic cells to initiate PanIN formation remains to be explored. Here, we use an optic-clear 3D histology to analyze the entire pancreas of 2-week-old PDX1-Cre; LSL-KrasG12D/+ mice to define the earliest PanIN and observe that the occurrence is independent of physical location. Instead, we found that the earliest PanIN cells overexpress Muc4 and associate with alpha-SMA+ fibroblast in both KrasG12D/+ transgenic mice as well as in human pancreatic specimens. Mechanistically, oncogenic KrasG12D, through genetic alterations, up-regulates Muc4 expression to increase proliferation, and Activin A secretion to activate/recruit fibroblast, and consequentially enhances cell transformation for PanIN formation. The interplay between oncogenic KrasG12D-mediated genetic alterations and induced microenvironmental changes appears to be essential for PanIN initiation, providing a clue for developing early diagnosis and prevention strategy for PDAC.