The E3 ubiquitin ligase TRIP12 is required for pancreatic acinar cell plasticity and the development of pancreatic cancer.

The protein TRIP12 (Thyroid hormone Receptor Interacting Protein 12) is an E3 ubiquitin ligase which the main function is to induce the degradation of targeted proteins. Our previous work revealed its role in the degradation of the PTF1A protein essential for acinar differentiation state However, TRIP12 implication in pancreatic carcinogenesis was not been completely demonstrated. Herein, we demonstrate that TRIP12 protein is markedly overexpressed in human pancreatic preneoplastic lesions and in human cancer samples. Acinar-to-ductal cell metaplasia (ADM) is a reversible process that reflects the high plasticity of acinar cells. ADM becomes irreversible in the presence of oncogenic Kras mutations and leads to the formation of preneoplastic lesions. Using two murine models, we showed that a loss of TRIP12 prevents acini from developing ADM. With two additional murine models, we further showed that a depletion of TRIP12 prevents the formation of preneoplastic lesions and impairs metastasis formation. Our study identifies an overexpression of TRIP12 from the early stages of pancreatic carcinogenesis and proposes this E3 ubiquitin ligase as a novel regulator of acinar plasticity with an important dual role in initiation and metastatic steps of PDAC.

The aim of this work is to share these mouse models and cell lines with the scientific community as a whole, in order to gain a better understanding of the importance of this protein in the development of pancreatic cancer.

Collaborations and partnerships

Collaborations :

• Laetitia Pieruccioni-Centre de recherches RESTORE, Université de Toulouse, INSERM, CNRS, EFS, ENVT, Toulouse, France
• Florence Capilla-Service d’Histopathologie expérimentale, INSERM US006-CREFRE, Toulouse, France
• Janick Selves-Département de Pathologie, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
• Anne Couvelard-Département de Pathologie Beaujon-Bichat, Hôpital Bichat, APHP and Université Paris Cité, Paris, France

Founding :

• La Ligue contre le cancer
• La Fondation Toulouse Cancer-Santé
• L’Association Française pour la Recherche sur le Cancer du Pancréas
• Le Cancéropôle Grand Sud-Ouest.
• L’Université Paul Sabatier (Toulouse)
• L’Ecole Normale Supérieure (Paris).