I am leading a scientific group on MUC4 and pancreatic carcinogenesis. My work is aiming to propose MUC4 and its partner ErbB2 as therapeutic targets in pancreatic cancer by combining complementary research using in vitro, in vivo (preclinical transgenic mouse models) and ex vivo. I also develop project on functional interaction between MUC4 and ion channel TRPM7 and associated molecular mechanisms (PhD thesis Julie Auwercx, codirector: Pr Gautier, UPJV Amiens, France). Since 2021, we initiated an emerging project about chemoresistance of pancreatic neuroendocrine tumors (PhD thesis Arnaud Jannin, codirector: Dr Coppin, CANTHER)

Key words : MUC4, ErbB2, TRPM7, pancreatic cancer, chemoresistance, metabolism

Pancreatic Ductal Adenocarcinoma (PDAC) cancer is the 4^th leading cause of death by cancer in the world with an extremely low survival rate (6 months) and a short survival curve at 5 years (3%). The lack of early diagnosis and efficient therapy leads to this dramatic outcome. It is urgent to develop new diagnostic and/or prognostic tools for the clinicians in order to propose better healthcare management of the disease. Moreover, identification of new molecular targets by deciphering the molecular mechanisms underlying the disease will allow the development of both new therapeutic tools and new therapeutic approaches to treat the disease.

MUC4 is high molecular weight glycoprotein that belongs to the membrane-bound mucin class. MUC4 is expressed at the surface of epithelial cells from gastrointestinal and respiratory tracts. MUC4 is normally not expressed in healthy pancreas. However, MUC4 expression is detected in the earliest lesion PanIN-1A and will be sustained in the carcinogenetic sequence. Pancreatic cancer has been the favored pathological model to decipher MUC4 biological roles. MUC4 promotes proliferation, invasion and chemoresistance in vitro and accelerates in vivo tumor growth. Thus, MUC4 could be a major actor of pancreatic carcinogenesis and a promising therapeutic target.

This project aims to understand the roles of MUC4 and ErbB2 and the cellular underlying mechanims in pancreatic carcinogenesis. We are using a triple (in vitro, in vivo and ex vivo) approach to decipher the role of these genes. In the recent years, we studied the MUC4 role in pancreatic carcinogenesis in which we showed for the first time the direct interaction of human MUC4 with human ErbB2 (Jonckheere et al., PLoS one 2012) and about MUC4 role and cellular mechanisms in chemotherapy resistance (Skrypek et al., Oncogene 2012). We also deciphered MUC4 regulation in pancreatic cancer by TGF-β (Jonckheere et al., Oncogene 2004), miRNA (Lahdaoui et al., Oncogene 2015) and K-RasG12D mutation (Vasseur et al., BBA Gene Reg Mech 2015).

I am trying to answer two questions:

• What is MUC4 doing in early stage of pancreatic carcinogenesis? (new biomarker? new tool?)
• What is the role of MUC4 in chemoresistance? (and how can we fight it?)