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Genome wide analysis in breast cancer organoids reveal pathways involved in hormone-dependent gene regulation

AuthorsRamirez-Cuellar, A. Julieta; Carbonell‐Caballero, José; Vicent, Guillermo P.; Beato, Miguel
Issue Date18-Nov-2019
CitationSignalling and Gene Regulation in Health & Disease (2019)
AbstractBreast cancer is a highly heterogeneous disease, dictated mainly by the spatial and temporal relation between the tumour and the microenvironment. The microenvironment of a cell is an organized combination of extracellular matrix, neighbouring cells, and interstitial fluid that influence cellular function (Warrick, 2008). However, how these external signals integrate and impact on gene regulation is far from understood, as most studies have been carried out in cells cultivated as monolayers on plastic. Organoids aim at recapitulating normal and pathological tissue conformation, structure and function, and are increasingly used. We aim to elucidate how the signalling network mediating hormone response differs in an organoid system from what has been found in conventional 2D culture, focusing on coordination of chromatin remodelling and differential gene expression in the control of cell proliferation and cell fate decisions. We have established the culture conditions for growing organoids from breast cancer cells. Initial work is performed with T47D cells exhibit hormone-dependent cell proliferation. The expression of hormone receptors and the hormone- dependent activation of Src/Ras/Erk kinase signalling pathway (Vicent et al., 2006) are comparable in organoids and 2D culture conditions, indicating an initial similar response to the hormonal stimulus. However, RNA-seq in the presence and absence of progestin R5020 shows 2,000 new differentially regulated genes in 3D. Surprisingly, ChIP-seq of PR in 3D shows a highly-reduced number of PR binding sites down to 16 % from the original described in 2D (Ballaré, 2013). ATAC-seq detected an overall reduced chromatin accessibility in 3D organoids, limiting PR binding to regions that are occupied at very low hormone concentration. Monitoring the genome architecture using Hi-C will help track the reorganization of the 3D nucleus resembling the physiological situation. This will allow us to identify new physiologically significant signalling pathways controlled by the microenvironment.
DescriptionTrabajo presentado en el Signalling and Gene Regulation in Health & Disease, celebrado en Cambridge (Gran Bretaña), los días 18 y 19 de noviembre de 2019
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