Co-targeting an AMPK–MAPK axis reprograms fibroblasts and suppresses PDAC

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Abstract
SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer characterized by limited therapeutic options and a highly treatment-resistant tumor microenvironment. Beyond tumor-intrinsic genetic alterations, growing evidence indicates that host–microbiome interactions influence cancer progression through microbial metabolites. However, how microbiome-derived metabolites influence oncogenic signaling in PDAC remains unclear. Here, integrated profiling revealed a consistent reduction of the microbial metabolite acetic acid in fecal samples from treatment-naïve patients with PDAC and in a genetically defined Drosophila model recapitulating key PDAC driver alterations. Acetic acid activates AMP-activated protein kinase, and pharmacological activation of this pathway together with inhibition of mitogen-activated protein kinase signaling suppressed tumor growth in fly and mouse models. Combined pathway targeting restored AMPK activity and suppressed cancer-associated fibroblast activation. These findings identify a microbiome-associated metabolic vulnerability in PDAC and suggest that coordinated targeting of metabolic and oncogenic signaling may restrain tumor progression and improve therapeutic strategies.
Funding Information
  • Suzuken Memorial Foundation
  • Extramural Collaborative Research Grant of Cancer Research Institute at Kanazawa University
  • Takeda Science Foundation
  • Suhara Memorial Foundation
  • Ono Medical Research Foundation
  • NOVARTIS Foundation for the Promotion of Science
  • Daiichi-Sankyo ‘Habataku’ Support Program for the Next Generation of Researchers
  • The Japanese Cancer Association
  • Kobayashi Foundation for Cancer Research
  • Japan Agency for Medical Research and Development-Core Research for Evolutionary Science and Technology
  • JST-Exploratory Research for Advanced Technology
  • the Food Science Institute Foundation
  • G-7 scholarship Foundation
  • The Junior Scientist Promotion and Photo-Excitonix projects at Hokkaido University
  • The Joint Research Program of the Institute for Genetic Medicine, Hokkaido University

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