Le vendredi 24 mai 2024, Monsieur Raphaël PEIFFER, titulaire d'un Master en sciences biomédicales à finalité approfondie et d'un Certificat de formation à la recherche en sciences biomédicales et pharmaceutiques, présentera l'examen en vue de l'obtention du grade de Doctorat en sciences biomédicales et pharmaceutiques, sous la direction de Monsieur Olivier PEULEN.

Cette épreuve consistera en la défense publique d'une thèse intitulée : "Myoferlin participates in TGFß-receptor trafficking in cancer-associated fibroblasts, promoting tumor desmoplasia and aggressiveness in pancreatic cancer".

Le jury sera composé de :

Michael HERFS (Président), Christophe DEROANNE (Secrétaire), Patrick JACQUEMIN (UCLouvain), Guy JERUSALEM, Claus JORGENSEN (Univ. Manchester), Elisabeth LETELLIER (Univ. Luxembourg), Denis MOTTET, Olivier PEULEN.

Résumé de la thèse :

Myoferlin is a membrane protein, overexpressed in pancreatic cancer (PAAD), and linked to several pro-oncogenic functions in pancreatic cancer cells. However, a potential role of myoferlin in the abundant pancreatic stroma has never been described.

First, using whole-tumor RNAseq data and IHC staining of PAAD patient biopsies, we found that MYOFhigh patients presented increased extracellular matrix (ECM) production and tumor fibrosis (desmoplasia) when compared to MYOFlow patients. Profiting from human and murine PAAD scRNAseq data we then identified myoferlin as highly expressed in cancer-associated fibroblasts (CAFs). Importantly, myoferlin was expressed in the TGFß-dependent myofibroblast-like CAF subtype (myCAFs), responsible for tumor desmoplasia. Further, using 2D and 3D in vitro models for myCAFs, we performed shRNA-mediated myoferlin knockdown. Strikingly, MYOFKD myCAFs had reduced gene expression and protein synthesis of all major PAAD ECM components. Mechanistically, we unveiled disrupted SMAD2/3-mediated TGFß signaling as cause for impaired ECM production. In fact, MYOFKD led to a block of TGFß-receptor 1 trafficking between the endoplasmic reticulum and Golgi apparatus, responsible for reduced TGFß-receptor 1 activity and impaired TGFß signaling. For clinical relevance, MYOFKD reduced tumor-promoting stroma features, such as myCAF contraction and migration, while PAAD patients with low stromal myoferlin abundance presented significantly improved survival.