[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Peiffer, Raphaël ; Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium ; Personalized Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
Laverdeur, Emilie ; Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
Boumahd, Yasmine; Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
Gullo, Charlotte; Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
Rademaker, Gilles; Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium ; Department of Anatomy, University of California, San Francisco, CA, USA
Crake, Rebekah; Laboratory of Tumor Biology and Development, GIGA Cancer, University of Liège, Liège, Belgium
Lavergne, Arnaud ; GIGA Bioinformatics Platform, University of Liège, Liège, Belgium
Maloujahmoum, Naïma; Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
Agirman, Ferman; Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
Herfs, Michael ; Laboratory of Experimental Pathology, GIGA Cancer, University of Liège, Liège, Belgium
Masamune, Atsushi ; Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
LETELLIER, Elisabeth ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Health, Medicine and Life Sciences (DHML)
Bellahcène, Akeila ; Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
Peulen, Olivier ; Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium. olivier.peulen@uliege.be
Fonds Léon Fredericq Université de Liège Fonds De La Recherche Scientifique - FNRS Japan Society for the Promotion of Science London Televie Fonds National de la Recherche Luxembourg
Funding text :
We kindly thank all patients that donated samples and made the human aspects of this study possible. The authors express their acknowledgement to the excellent support provided by the institutional Biobank (BHUL), the ULi\u00E8ge animal housing staff and GIGA technical facilities (University of Li\u00E8ge). Notably, Dr. Chantal Humblet from the Histology platform, Dr. Emmanuel Di Valentin with M. Francois Giroulle and Ms. Alexandra Revnic from the Viral Vectors platform, Dr. Sandra Ormenese with M. Alexandre Hego and M. Ga\u00EBtan Lefevre from the GIGA-Imaging platform, Dr. Wouter Coppieters from the Genomics platform, Dr. Arnaud Lavergne from the Bioinformatics platform. We also thank Dr. Helene Pendeville-Samain from the Gene Editing platform for the generation of Myof KO mice via CRISPR. Furthermore, authors thank Dr. Jonas Van Audenaerde (UAntwerpen, Belgium) for gifting KPC cells and Prof. Patrick Jacquemin with Ms. Margaux Wulleman (De Duve Institute, UCLouvain, Belgium) for technical guidance with orthotopic pancreas transplantations in mice. The authors also thank M. Patrick Roncarati for assistance with QuPath image analysis. Finally, authors thank M. Louis Baudin (Animascience) for the design of the graphical summary. The results in this work are in part based on data generated by the TCGA Research Network: www.cancergenome.nih.gov. This work was supported by the \u201CFondation L\u00E9on Fr\u00E9dericq\u201D, the Julia Russe prize, the University of Li\u00E8ge \u201CFonds sp\u00E9ciaux cr\u00E9dits sectoriels (CSRV-SS)\u201D and the \u201CFonds de la Recherche Scientifique (FNRS)\u201D grant N\u00B0 J.0167.24. RP is a Research Fellow (FNRS, grant N\u00B0 40010385), RC is a \u201CT\u00E9l\u00E9vie\u201D postdoctoral fellow, GR is a Postdoctoral Researcher (FNRS, grant 40024125), MH is a Research Associate (FNRS) and AB is a Research Director (FNRS). EL and AG are supported by the Luxembourg National Research Fund (FNR). AM is supported by a JSPS KAKENHI grant (N\u00B0 23K24312).We kindly thank all patients that donated samples and made the human aspects of this study possible. The authors express their acknowledgement to the excellent support provided by the institutional Biobank (BHUL), the ULi\u00E8ge animal housing staff and GIGA technical facilities (University of Li\u00E8ge). Notably, Dr. Chantal Humblet from the Histology platform, Dr. Emmanuel Di Valentin with M. Francois Giroulle and Ms. Alexandra Revnic from the Viral Vectors platform, Dr. Sandra Ormenese with M. Alexandre Hego and M. Ga\u00EBtan Lefevre from the GIGA-Imaging platform, Dr. Wouter Coppieters from the Genomics platform, Dr. Arnaud Lavergne from the Bioinformatics platform. We also thank Dr. Helene Pendeville-Samain from the Gene Editing platform for the generation of Myof mice via CRISPR. Furthermore, authors thank Dr. Jonas Van Audenaerde (UAntwerpen, Belgium) for gifting KPC cells and Prof. Patrick Jacquemin with Ms. Margaux Wulleman (De Duve Institute, UCLouvain, Belgium) for technical guidance with orthotopic pancreas transplantations in mice. The authors also thank M. Patrick Roncarati for assistance with QuPath image analysis. Finally, authors thank M. Louis Baudin (Animascience) for the design of the graphical summary. The results in this work are in part based on data generated by the TCGA Research Network: www.cancergenome.nih.gov . This work was supported by the \u201CFondation L\u00E9on Fr\u00E9dericq\u201D, the Julia Russe prize, the University of Li\u00E8ge \u201CFonds sp\u00E9ciaux cr\u00E9dits sectoriels (CSRV-SS)\u201D and the \u201CFonds de la Recherche Scientifique (FNRS)\u201D grant N\u00B0 J.0167.24. RP is a Research Fellow (FNRS, grant N\u00B0 40010385), RC is a \u201CT\u00E9l\u00E9vie\u201D postdoctoral fellow, GR is a Postdoctoral Researcher (FNRS, grant 40024125), MH is a Research Associate (FNRS) and AB is a Research Director (FNRS). EL and AG are supported by the Luxembourg National Research Fund (FNR). AM is supported by a JSPS KAKENHI grant (N\u00B0 23K24312).
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