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

Abstract : 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.
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https://hal.umontpellier.fr/hal-02284709
Contributeur : Nathalie Salvy-Cordoba <>
Soumis le : jeudi 12 septembre 2019 - 09:52:49
Dernière modification le : samedi 14 septembre 2019 - 01:19:23

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Nicolas Chuvin, David Vincent, Roxane Pommier, Lindsay 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, Philadelphia, PA : American Gastroenterological Association, [2015]-, 2017, 4 (2), pp.263-282. ⟨10.1016/j.jcmgh.2017.05.005⟩. ⟨hal-02284709⟩

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