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. 2025 Oct 8.
doi: 10.1038/s44318-025-00570-6. Online ahead of print.

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

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
Free article

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

Raphaël Peiffer et al. EMBO J. .
Free article

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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Conflict of interest statement

Disclosure and competing interests statement. The authors declare no competing interests.

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