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

Hui-Ju Wen1, Erick T Davis1, Jacee S Moore1

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Cellular and Molecular Gastroenterology and Hepatology
|December 22, 2025
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Summary

A Disintegrin and Metalloproteinase 17 (ADAM17) is crucial for pancreatic cancer initiation and progression by regulating signaling pathways and the tumor microenvironment. Inhibiting ADAM17 can revert precancerous lesions and halt tumor growth, even with oncogenic KRAS.

Keywords:
Acinar Cell TransdifferentiationEGFREGFR Ligand SheddaseMacrophageNeoplasia

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • ADAM17 is a sheddase regulating signaling molecules like inflammatory mediators and EGFR ligands.
  • EGFR activation drives pancreatic acinar cell transdifferentiation, a precursor to neoplasia in KRASG12D-driven pancreatic cancer.
  • The role of ADAM17 in tumor and myeloid cells in pancreatic cancer initiation and progression is not fully understood.

Purpose of the Study:

  • To investigate the contribution of ADAM17 in tumor and myeloid cells to pancreatic cancer initiation and progression.
  • To understand the mechanisms by which ADAM17 influences epithelial plasticity and the tumor microenvironment.

Main Methods:

  • Generated mouse models with parenchymal or myeloid-specific ADAM17 gene ablation in the context of KRASG12D-driven pancreatic tumorigenesis.
  • Utilized dual recombinase mouse models to specifically delete ADAM17 in myeloid cells.
  • Administered an ADAM17-blocking antibody to treat established KRASG12D-driven pancreatic tumors.

Main Results:

  • Parenchymal deletion of ADAM17 blocked KRASG12D-induced metaplasia/neoplasia and reduced macrophage infiltration.
  • Myeloid ADAM17 ablation impeded neoplastic progression but did not prevent initial metaplasia.
  • ADAM17 inhibition reverted premalignant lesions, resolved fibro-inflammatory responses, and compromised oncogenic signaling.

Conclusions:

  • ADAM17 is essential for KRASG12D-driven pancreatic tumorigenesis, regulating both autocrine and paracrine signaling.
  • ADAM17 promotes neoplastic progression by modulating EGFR signaling and the fibroinflammatory microenvironment.
  • ADAM17 plays a pivotal role in orchestrating epithelial plasticity, signaling, and stromal remodeling in pancreatic cancer.