Oncogenic KRAS, Mucin 4, and Activin A-Mediated Fibroblast Activation Cooperate for PanIN Initiation.

ABSTRACT: Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic-clear 3D histology is used to analyze entire pancreases of 2-week-old Pdx1-Cre; LSL-Kras^G12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA⁺ fibroblasts in both transgenic mice and human specimens. Mechanistically, Kras^G12D/+ pancreatic cells upregulate Muc4 through gene

SUBMITTER: Hu CM 

PROVIDER: S-EPMC10754145 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature