Oral Presentation 37th Lorne Cancer Conference 2025

Targeting myoferlin-dependent ER/Golgi vesicle trafficking reprograms cancer-associated fibroblasts and tackles stromal aggressiveness in pancreatic cancer. (112910)

Raphael Peiffer 1 2 , 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 1
  1. Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
  2. Now with: Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, 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

Intracellular vesicle trafficking is an evolutionary conserved process implicated in a great variety of cellular functions and diseases. Pancreatic cancer cells exploit vesicle trafficking via the Golgi apparatus to support cellular flexibility and tumor aggressiveness by relying on vesicle-trafficking proteins such as myoferlin. However, our understanding of myoferlin-dependent vesicle trafficking is limited to cancer cells, while the function of myoferlin in the pancreatic tumor microenvironment, notably cancer-associated fibroblasts (CAFs), has been overlooked.

Here we combine pancreatic adenocarcinoma (PAAD) whole-tumor and single-cell transcriptomic analyses with immunohistochemistry to link stromal myoferlin to tumor aggressiveness. Using 2D and 3D in vitro models of human CAFs, we unveil CAF-specific functions of myoferlin, as MYOF-depleted (MYOFKD) CAFs present impaired activity and reduced extracellular matrix (ECM) production. Analysis of intracellular vesicles in MYOFKD CAFs identifies myoferlin as novel functional member of COP2-coated vesicle trafficking between the endoplasmic reticulum (ER) and Golgi apparatus. Accordingly, MYOFKD causes a TGFß-receptor 1 (TGFBR1) trafficking blockade at the ER/Golgi interface, leading to altered TGFBR1 activation, impaired TGFß signal transduction, loss of ECM production and reduced stroma aggressiveness. Orthotopic transplantation of MYOFKD CAFs with pancreatic cancer cells in mice impairs tumor establishment, while pharmacological targeting of myoferlin reduces tumor desmoplasia in tumor-bearing mice without increasing tumor burden.

Overall, we propose TGFBR1 trafficking, druggable via myoferlin, as novel approach to interfere with signal transduction and to reprogram CAFs. Thus, enabling to efficiently tackle desmoplasia and to control stromal aggressiveness. The translational outlook of these findings is underpinned by the driving role of tumor desmoplasia during therapy resistance and immune exclusion in pancreatic cancer.