Oncogenic KRAS, Mucin 4, and Activin A-Mediated Fibroblast Activation Cooperate for PanIN Initiation
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Journal Volume
10
Journal Issue
36
Date Issued
2023-12
Author(s)
Hu, Chun-Mei
Huang, Chien-Chang
Hsu, Min-Fen
Chien, Hung-Jen
Wu, Pei-Jung
Chen, Yi-Ing
Tang, Shiue-Cheng
Chung, Mei-Hsin
Shen, Chia-Ning
Lee, Wen-Hwa
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-KrasG12D/+ (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, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+ -driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.
Subjects
Kras
Muc4
PanIN
activin A
αSMA+ fibroblast
SDGs
Type
journal article