ADAM17-dependent Autocrine and Paracrine Signaling Promotes Pancreatic Premalignant Progression
Recommended Citation
Wen HJ, Davis ET, Moore JS, Brender SM, Benitz S, Wombwell AM, Loveless IM, Long DW, Salas-Escabillas DJ, Lee J, Devorkin BS, McQuithey H, Steele NG, Hurt E, and Crawford HC. ADAM17-dependent autocrine and paracrine signaling promotes pancreatic premalignant progression. Cell Mol Gastroenterol Hepatol 2025;20(4):101711.
Document Type
Article
Publication Date
12-20-2025
Publication Title
Cell Mol Gastroenterol Hepatol
Keywords
Animals, ADAM17 Protein, Pancreatic Neoplasms, Mice, Paracrine Communication, Disease Progression, Precancerous Conditions, Autocrine Communication, Humans, Disease Models, Animal, Proto-Oncogene Proteins p21(ras), Pancreas, ErbB Receptors, Myeloid Cells, Carcinoma, Pancreatic Ductal
Abstract
BACKGROUND AND AIMS: A Disintegrin and Metalloproteinase 17 (ADAM17) is a membrane-bound sheddase that regulates the release of multiple signaling molecules, including inflammatory mediators and EGFR ligands. Ligand-driven EGFR activation is essential for pancreatic acinar cell transdifferentiation into metaplastic ducts, which progress to neoplasia in the presence of oncogenic Kras(G12D). The aim of this study is to understand how ADAM17 in the tumor and myeloid cells contribute to the initiation and progression of pancreatic tumors.
METHODS: KRAS(G12D)-driven pancreatic tumorigenesis models with parenchymal gene ablation (Egfr(f/f);Kras(LSL-G12D/+);Ptf1a(Cre/+) and Adam17(f/f);Kras(LSL-G12D/+);Ptf1a(Cre/+) ) and dual recombinase mouse models with Kras(G12D) expression in the parenchyma and gene deletion in myeloid cells (Kras(FSF-G12D/+);Ptf1a(FlpO/+);LysM-Cre;Adam17(f/ff)) were generated to investigate the functional contributions of ADAM17 in different cell types. An intervention study using an ADAM17-blocking antibody to treat Kras(LSL-G12D/+);Ptf1a(Cre/+) mice after tumor initiation.
RESULTS: Genetic deletion of Adam17 in pancreatic parenchymal cells blocked KRAS(G12D)-induced metaplasia/neoplasia and inhibited macrophage infiltration. Ablation of Adam17 in myeloid cells did not prevent initial metaplastic duct formation but impeded neoplastic progression. Pharmacological inhibition of ADAM17 compromised multiple oncogenic signaling cascades, reverted premalignant ductal lesions to an acinar state, and resolved the fibro-inflammatory response, despite continued KRAS(G12D) expression.
CONCLUSIONS: KRAS(G12D)-driven tumorigenesis requires both autocrine and paracrine signaling regulated by ADAM17. Beyond activating EGFR to drive acinar cell transdifferentiation, ADAM17 also promotes neoplastic progression by modulating additional protumor signaling that shape the fibroinflammatory microenvironment. These findings highlight a pivotal role for ADAM17 in orchestrating epithelial plasticity, cellular signaling, and stromal remodeling during pancreatic tumorigenesis.
Medical Subject Headings
Animals; ADAM17 Protein; Pancreatic Neoplasms; Mice; Paracrine Communication; Disease Progression; Precancerous Conditions; Autocrine Communication; Humans; Disease Models, Animal; Proto-Oncogene Proteins p21(ras); Pancreas; ErbB Receptors; Myeloid Cells; Carcinoma, Pancreatic Ductal
PubMed ID
41429223
ePublication
ePub ahead of print
Volume
20
Issue
4
First Page
101711
Last Page
101711
