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Mécanismes épigénétiques et réponse des cellules cancéreuses au microenvironnement : implication de la méthylation de l’ADN et de l’un de ses interprètes, MBD2

Abstract : Breast cancers develop in complex tissue environments where cancer associated fibroblasts (CAF) play a crucial role in tumorigenesis by secreting various growth factors, cytokines, proteases and extracellular matrix components. Soluble factors secreted by CAFs are involved in many pathways including inflammation, metabolism, proliferation, and epigenetic modulation suggesting that CAF-dependent reprograming of cancer cells affects a large set of genes. From RNAseq data obtained from breast cancer cell lines grown in presence of CAF-secreted factors, we identified 372 upregulated genes exhibiting an expression level positively correlated with the stromal content of breast cancer specimens. Furthermore, we observed that gene expression changes were not mediated through significant DNA methylation changes. Nevertheless CAF-secreted factors but also stromal content of the tumors remarkably activated specific genes characterized by a DNA methylation signature: hypermethylation at transcription start site (TSS) and shore regions. Experimental approaches (inhibition of DNA methylation, knockdown of MBD2, and ChIP assays) demonstrated the implication of DNA methylation and methyl DNA binding protein in the response of cancers cells to CAF-secreted factors. These data put in light the importance of epigenetics marks in the cancer cell reprogramming induced by stromal cell and indicate that the interpreters of the DNA methylation signal play a major role in the response of the cancer cells to the microenvironment
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Pauline Mathot. Mécanismes épigénétiques et réponse des cellules cancéreuses au microenvironnement : implication de la méthylation de l’ADN et de l’un de ses interprètes, MBD2. Cancer. Université de Lyon, 2017. Français. ⟨NNT : 2017LYSE1163⟩. ⟨tel-01684805⟩

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