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Verteporfin targeting YAP1/TAZ‐TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells

Abstract : Gastric carcinomas (GC) are heterogeneous tumors, composed of a subpopulation of cluster of differentiation-44 (CD44)+ tumorigenic and chemoresistant cancer stem cells (CSC). YAP1 and TAZ oncoproteins (Y/T) interact with TEA domain family member 1 (TEAD) transcription factors to promote cell survival and proliferation in multiple tissues. Their activity and role in GC remain unclear. This work aimed to analyze Y/T-TEAD activity and molecular signature in gastric CSC, and to assess the effect of verteporfin, a Food and Drug Administration-approved drug preventing Y/T-TEAD interaction, on gastric CSC tumorigenic properties. Y/T-TEAD molecular signature was investigated using bioinformatical (KmPlot database), transcriptomic and immunostaining analyses in patient-derived GC and cell lines. Verteporfin effects on Y/T-TEAD transcriptional activity, CSC proliferation and tumorigenic properties were evaluated using in vitro tumorsphere assays and mouse models of patient-derived GC xenografts. High expressions of YAP1, TAZ, TEAD1, TEAD4 and their target genes were associated with low overall survival in nonmetastatic human GC patients (n = 444). This Y/T-TEAD molecular signature was enriched in CD44+ patient-derived GC cells and in cells resistant to conventional chemotherapy. Verteporfin treatment inhibited Y/T-TEAD transcriptional activity, cell proliferation and CD44 expression, and decreased the pool of tumorsphere-forming CD44+ /aldehyde dehydrogenase (ALDH)high gastric CSC. Finally, verteporfin treatment inhibited GC tumor growth in vivo; the residual tumor cells exhibited reduced expressions of CD44 and ALDH1, and more importantly, they were unable to initiate new tumorspheres in vitro. All these data demonstrate that Y/T-TEAD activity controls gastric CSC tumorigenic properties. The repositioning of verteporfin targeting YAP1/TAZ-TEAD activity could be a promising CSC-based strategy for the treatment of GC.
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Contributor : Christine Varon Connect in order to contact the contributor
Submitted on : Friday, November 13, 2020 - 6:18:33 PM
Last modification on : Sunday, June 26, 2022 - 2:56:52 AM

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Julie Giraud, Silvia Molina‐castro, Lornella Seeneevassen, Elodie Sifré, Julien Izotte, et al.. Verteporfin targeting YAP1/TAZ‐TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells. International Journal of Cancer, Wiley, 2019, 146 (8), pp.2255-2267. ⟨10.1002/ijc.32667⟩. ⟨inserm-03004854⟩



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