ADAM17-dependent Autocrine and Paracrine Signaling Promotes Pancreatic Premalignant Progression.

BACKGROUND & AIMS: A Disintegrin and Metalloproteinase 17 (ADAM17) is a membrane-bound sheddase that regulates the release of multiple signaling molecules, including inflammatory mediators and epidermal growth factor receptor (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 was conducted. 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 pro-tumor signaling that shapes the fibroinflammatory microenvironment. These findings highlight a pivotal role for ADAM17 in orchestrating epithelial plasticity, cellular signaling, and stromal remodeling during pancreatic tumorigenesis.