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Novel function of the ER stress transducer IRE1α in cell migration and invasion of metastatic melanoma cells

Abstract : Tumor cells are exposed to cell-intrinsic and extrinsic perturbations that alter the proper functioning of the endoplasmic reticulum (ER); a cellular condition known as ER stress. This condition engages an adaptive response termed as unfolded protein response (UPR). IRE1 is the most evolutionary conserved ER stress sensor of the UPR. Activation of the IRE1 RNase activity controls the expression of the transcription factor XBP1s and the degradation of mRNA through a process termed RIDD. IRE1 activity has been linked to cell migration and invasion in different types of tumors. However, no evidence regarding the role of IRE1 in melanoma cell migration/invasion has been published. Importantly in 2018 our group described a novel function of IRE1 independent of its catalytic activity, where IRE1 acted as a scaffold favoring cell migration through FLNA, an actin crosslinking protein involved in cell migration. This was demonstrated in non-tumoral cells. Therefore, in this thesis, we initially aimed to uncover the contribution of IRE1/FLNA signaling in cell migration and invasion in melanoma cells, its impact on the metastatic process. By using genetic and pharmacologic approaches, we found that deficiency of IRE1 expression or RNase activity inhibition enhances cell migration and invasion of human metastatic melanoma cell lines, indicating that the IRE1 branch could be acting as a suppressor of cell migration and invasion in metastatic melanoma cells. Notably, we were not able to corroborate the IRE1-dependent phosphorylation of FLNA. Importantly, processes that are known to be regulated by FLNA like actin cytoskeleton and cell adhesion were not affected by IRE1 depletion in human metastatic melanoma cells. These findings suggest that the regulation of cell migration/invasion by IRE1 is an FLNA-independent mechanism. Analyzing a gene expression database of melanoma tumors, we found that tumors identified with high RIDD activity presented a significant decrease in the expression of genes involved in melanoma metastasis. Our findings suggest that IRE1 through RIDD acts as a suppressor of metastatic melanoma cell migration and invasion. The results obtained in this thesis constitute the first approximation on the implication of IRE1 in metastasis-related processes in melanoma, such as cell migration and invasion.
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Submitted on : Wednesday, February 23, 2022 - 11:14:42 AM
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  • HAL Id : tel-03585530, version 1


Celia María Limia León. Novel function of the ER stress transducer IRE1α in cell migration and invasion of metastatic melanoma cells. Human health and pathology. Université Rennes 1, 2021. English. ⟨NNT : 2021REN1B015⟩. ⟨tel-03585530⟩



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