Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRAS G12D -driven Pancreatic Tumorigenesis

Nicolas Chuvin (1) , David Vincent (1) , Roxane Pommier (1) , Lindsay B Alcaraz (1) , Johann Gout (1) , Cassandre Caligaris (1) , Karam Yacoub (1) , Victoire Cardot (2, 1) , Elodie Roger (3, 1) , Bastien Kaniewski (1) , Sylvie Martel (4, 1) , Celia Cintas (5) , Sophie Goddard-Léon (1) , Amélie Colombe (1) , Julie Valantin (1) , Nicolas Gadot (1) , Emilie Servoz (1) , Jennifer Morton (6) , Isabelle Goddard (1) , Anne Couvelard (7) , Vinciane Rebours (8) , Julie Guillermet (5) , Owen Sansom (6) , Isabelle Treilleux (1) , Ulrich Valcourt (1) , Stéphanie Sentis (4, 1) , Pierre Dubus (9, 10) , Laurent Bartholin (1)

1 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
2 RDP - Reproduction et développement des plantes
3 UA - Université d'Artois
4 Oncogénèse et progression tumorale
5 CRCT - Centre de Recherches en Cancérologie de Toulouse
6 The Beatson Institute for Cancer Research
7 Département d'Anatomo-Pathologie [Hôpital Bichat]
8 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
9 Histologie et Pathologie Moléculaire des Tumeurs
10 Epidémiologie et Biostatistique [Bordeaux]

Transforming growth factor beta (TGFβ) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFβ-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive. We developed a transgenic mouse model allowing tamoxifen-inducible and Cre-mediated conditional activation of a constitutively active type I TGFβ receptor (TβRICA) in the pancreatic acinar compartment. We observed that TβRICA expression induced acinar-to-ductal metaplasia (ADM) reprogramming, eventually facilitating the onset of KRASG12D-induced pre-cancerous pancreatic intraepithelial neoplasia. This phenotype was characterized by the cellular activation of apoptosis and dedifferentiation, two hallmarks of ADM, whereas at the molecular level, we evidenced a modulation in the expression of transcription factors such as Hnf1β, Sox9, and Hes1.

Mots clés: Pancreas Cancer TGFβ Acinar-to-Ductal Metaplasia KRASG12D

Domaines: Cancer

Nicolas Chuvin, David Vincent, Roxane Pommier, Lindsay B Alcaraz, Johann Gout, et al.. Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRAS G12D -driven Pancreatic Tumorigenesis. Cellular and Molecular Gastroenterology and Hepatology, 2017, 4 (2), pp.263-282. ⟨10.1016/j.jcmgh.2017.05.005⟩. ⟨hal-02284709⟩