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Rôle du Transforming Growth Factor-β (TGFβ) au cours de la tumorigenèse pancréatique

Abstract : The TGFβ (Transforming Growth Factor-β) belongs to a wide family of cytokinesinvolved in numerous functions during embryogenesis and adult life. During tumorigenesis,TGFβ is considered as a double-edge-sword preventing tumor initiation in normal orimmortalized epithelia but, in contrast, facilitating tumor progression in transformedepithelia. We have studied this dual functionality of TGFβ in Pancreatic DuctalAdenocarcinoma (PDAC), a devastating disease representing the fifth leading-cause ofrelated-cancer death in industrialized countries. Most of pancreatic cancers present activatingKras oncogene mutations, high expression level of secreted TGFβ and inactivating mutationsof affecting major mediators of the TGFβ signaling. The main objective of my thesis was tounderstand the role of TGFβ during pancreatic tumorigenesis using genetically modifiedmouse models, then mimicking the human disease. First, we showed that targeted activationof TGFβ signaling in the pancreas could cooperate with Kras oncogene to induce pancreatitis,an inflammation of the pancreas described as a tumor-promoting environment. Second, wedemonstrated the tumor suppressor role of TIF1γ, a protein recently involved in the TGFβsignaling. In conclusion, this work has contributed to a better understanding of the molecularmechanisms responsible for pancreatitis initiation. Our results open new therapeuticsperspectives leading to the inhibition of the TGFβ-mediated program of thus inhibiting prooncogeniceffect of pancreatitis. Moreover, we defined a new tumor suppressor pathwayactivated in the pancreas. The molecular characterization of programs engaged by TIF1γcould allow defining new therapeutic strategies.
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Submitted on : Tuesday, April 29, 2014 - 2:27:31 PM
Last modification on : Tuesday, October 19, 2021 - 11:07:41 PM
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David Vincent. Rôle du Transforming Growth Factor-β (TGFβ) au cours de la tumorigenèse pancréatique. Médecine humaine et pathologie. Université Claude Bernard - Lyon I, 2012. Français. ⟨NNT : 2012LYO10158⟩. ⟨tel-00985271⟩

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