• Sunday, 24 January 2021 - 09:37:15

Thesis : Cindy Lobe – Role of the transcription factor ZEB1 in the progression and chemoresistance of cholangiocarcinoma

September 24 - 2019

directed by Laura Fouassier

(Team Housset) — (started in the team Praz, previous term)

Summary: ZEB1 (Zinc finger E-box binding homeobox) is a transcription factor that promotes tumor invasion and metastasis by inducing an epithelial-mesenchymal transition (EMT) in carcinoma cells. MMT not only plays an important role in embryonic development and malignant progression, but is also involved in the acquisition of cancer stem cell (CSC) properties and resistance to treatment. The objective of this work was to study the involvement of ZEB1 in the progression and chemoresistance of CCA. Our previous work in the first article showed an overexpression of ZEB1 in cells resistant to anti-EGFR treatment in the CCA. Clinical data revealed an expression of ZEB1 in human samples of CCA and associated its expression with poor prognosis. For in vitro studies, different cellular study models were performed in which the expression of ZEB1 was either invalidated or forced. The results showed the involvement of ZEB1 in cellular plasticity characterized by the placement of a TEM and CSC phenotype in ZEB1 expressing cells compared to control cells. The invalidation models of ZEB1 showed inhibition of these processes. In addition, cell viability analyses identified ZEB1 as a resistance factor to anti-EGFR treatment in CCA models. The invalidation models of ZEB1 showed a re-sensitization of the cells to anti-EGFR treatment. In conclusion, we have demonstrated in this study that ZEB1 would contribute to the cellular plasticity and chemoresistance of CCA cells, making it a target of choice in the development of new therapeutic strategies in CCA.

Keywords: ZEB1, cholangiocarcinoma, epithelial-mesenchymal transition, tumor stem cells, resistance

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