Equipe d’Accueil : Hétérogénéité de la tumorigenèse pancréatique (PATH)

Intitulé de l’Unité : Inserm U1149 – Centre de Recherche sur l’Inflammation (CRI)

Nom du Responsable de l’Unité : Valérie PARADIS

Nom du Responsable de l’Équipe : Cécile HAUMAITRE / Jérôme CROS

Adresse :  Faculté de Médecine Bichat, 16 rue Henri Huchard, 75018 Paris

Responsable de l’encadrement : Cécile HAUMAITRE

Tél : 01 57 27 74 87    E-mail:  cecile.haumaitre@inserm.fr

Résumé du projet 

Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is projected to become the second leading cause of cancer death by 2030. The prognosis for PDAC remains extremely poor, with a 5-year survival rate of <10%. It arises from 2 distinct types of non-invasive precancerous lesions that are curable if detected early. Microscopic pancreatic intraepithelial neoplasia (PanIN) and macroscopic intraductal papillary mucinous neoplasia (IPMN). Understanding the molecular mechanisms underlying the development of these lesions and their transition to invasive carcinoma is essential to improve early detection and prognosis of PDAC.

IPMNs, defined as papillary growth of pancreatic ductal cells with mucin secretion, are macroscopic lesions characterized by dilated pancreatic ducts lined by dysplastic cells. They affect 5–10% of adults, with the prevalence increasing with age. Although not all IPMNs progress to cancer, their unpredictable evolution requires careful monitoring. The mechanisms driving the initiation and progression of IPMNs remain poorly understood.

We recently developped a mouse model (KHC model : Sox9-creER;LSL-KrasG12D;Hnf1bfl/fl;R26RYFP) that recapitulates the development of IPMN. We characterized this model histologically and molecularly (Lorenzo et al., bioRxiv 2025). To go further and deeper in the molecular understanding of IPMN initiation from ductal cells, we will perform a single cell scRNA-seq study on pancreatic ductal cells isolated by flow-cytometry with the YFP reporter present in our mouse model, using the split-pool ligation-based transcriptome sequencing (SPLITseq) from Parse Bioscience. This study will allow us to dissect the heterogeneity of ductal cell populations and trace their transformation during the early stages of IPMN. By identifying distinct transcriptional profiles and lineage trajectories, this approach would reveal key molecular mechanisms driving neoplastic initiation. This would help to identify new early biomarkers and potential therapeutic targets, offering valuable tools for improving monitoring and personalized management of patients with IPMN.

 

Dernières Publications en lien avec le projet : 

  • Lorenzo D, Aguilera Munoz L, Marstrand-Daucé L, Chassac A, Nicole P, Meng L, Heidet L, Knebelmann B, Pignolet C, Doblas S, Couvineau A, Esposito I, Rebours V, Nicolle R, Cros Jé, Couvelard A, Haumaitre C. Loss of HNF1b drives pancreatic Intraductal Papillary Mucinous Neoplasms (IPMN) initiation. BioRxiv 2025.06.12.659269; doi: https://doi.org/10.1101/2025.06.12.659269.
  • Lorenzo D, Aguilera Munoz L, Vedie AL, Prat F, Dokmak S, Sauvanet A, Maire F, de Mestier L, Copin P, Dioguardi Burgio M, Couvelard A, Haumaitre C, Cros J, Rebours V. Mural nodules and prevalence of high-grade dysplasia in branch duct intraductal papillary mucinous neoplasm of the pancreas undergoing resection. Br J Surg. 2024 Nov 27;111(12):znae292. doi: 10.1093/bjs/znae292. PMID: 39612583.
  • Marstrand-Daucé L, Lorenzo D, Chassac A, Nicole P, Couvelard A, Haumaitre C. Acinar-to-Ductal Metaplasia (ADM): On the Road to Pancreatic Intraepithelial Neoplasia (PanIN) and Pancreatic Cancer. Review. Int J Mol Sci. 2023 Jun 9;24(12):9946. doi: 10.3390/ijms24129946. PMID: 37373094.
  • Quilichini E, Fabre M, Nord C, Dirami T, Le Marec A, Cereghini S, Pasek RC, Gannon M, Ahlgren U, Haumaitre C. Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease. J Pathol. 2021 May;254(1):31-45.
  • Quilichini E, Fabre M, Dirami T, Stedman A, De Vas M, Ozguc O, Pasek RC, Cereghini S, Morillon L, Guerra C, Couvelard A, Gannon M, Haumaitre C. Pancreatic Ductal Deletion of Hnf1b Disrupts Exocrine Homeostasis, Leads to Pancreatitis, and Facilitates Tumorigenesis. Cell Mol Gastroenterol Hepatol. 2019;8(3):487-511.

   

Ce projet s’inscrit dans la perspective d’une thèse 

si oui type de financement prévu : Non

 Ecole Doctorale de rattachement :  BioSPC