2. Academic Validation
  3. Targeting myoferlin in ER/Golgi vesicle trafficking reprograms pancreatic cancer-associated fibroblasts

Targeting myoferlin in ER/Golgi vesicle trafficking reprograms pancreatic cancer-associated fibroblasts

  • EMBO J. 2025 Oct 8. doi: 10.1038/s44318-025-00570-6.
Raphaël Peiffer 1 2,  Emilie Laverdeur 1,  Anthoula Gaigneaux 3,  Yasmine Boumahd 1,  Charlotte Gullo 1,  Gilles Rademaker 1 4,  Rebekah Crake 5,  Arnaud Lavergne 6,  Naïma Maloujahmoum 1,  Ferman Agirman 1,  Michael Herfs 7,  Atsushi Masamune 8,  Elisabeth Letellier 3,  Akeila Bellahcène 1,  Olivier Peulen 9
Affiliations

Affiliations

  • 1 Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
  • 2 Personalized Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • 3 Molecular Disease Mechanisms Group, University of Luxembourg, Belvaux, Luxembourg.
  • 4 Department of Anatomy, University of California, San Francisco, CA, USA.
  • 5 Laboratory of Tumor Biology and Development, GIGA Cancer, University of Liège, Liège, Belgium.
  • 6 GIGA Bioinformatics Platform, University of Liège, Liège, Belgium.
  • 7 Laboratory of Experimental Pathology, GIGA Cancer, University of Liège, Liège, Belgium.
  • 8 Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
  • 9 Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium. olivier.peulen@uliege.be.
PMID: 41062852 DOI: 10.1038/s44318-025-00570-6
Abstract

Pancreatic adenocarcinoma (PAAD) cells exploit vesicle trafficking proteins, such as myoferlin (encoded by MYOF), to fuel tumor aggressiveness, yet the presence and function of myoferlin-dependent vesicles in cancer-associated fibroblasts (CAFs) remain unknown. By combining PAAD whole-tumor and single-cell transcriptomic analyses with immunohistochemistry and 2D/3D in vitro models, we link stromal myoferlin to tumor aggressiveness. We identify CAF-specific functions of myoferlin, as MYOF-depleted CAFs exhibit reduced activity and impaired extracellular matrix (ECM) production. Analysis of intracellular vesicles shows that myoferlin depletion results in a TGFß-receptor 1 (TGFBR1) trafficking blockade at the ER/Golgi interface upon myoferlin depletion, leading to altered TGFBR1 activation, impaired signal transduction, loss of ECM production and reduced CAF contractility. Both genetic depletion of myoferlin in the murine tumor stroma and the pharmacological targeting of myoferlin alike reduced tumor desmoplasia in orthotopic mouse model of pancreatic ductal adenocarcinoma. Based on these findings, we propose TGFBR1 trafficking as a potential target for reprogramming CAFs, controlling desmoplasia, and tackling these aggressive features in pancreatic Cancer.

Keywords

COPII-vesicle Trafficking; Cancer-associated Fibroblasts; Desmoplasia; Myoferlin; Pancreatic Cancer.

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