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Identification of the tumour transition states occurring during EMT [ATAC-seq]

ABSTRACT: EMT (epithelial-mesenchymal transition) in cancer has been associated with tumour stemness, metastasis and resistance to therapy. It has recently been proposed that, rather than being a binary process, EMT occurs through distinct intermediate states. However,direct in vivo evidence supporting this possibility is still lacking. By screening a large panel of cell surface markers, we identified the existence of multiple tumour subpopulations associated with different EMT stages from epithelial to completely mesenchymal states passing through intermediate hybrid states in skin and mammary primary tumours. Although all EMT subpopulations presented similar tumour propagating cell capacity, they displayed different, invasiveness and metastatic potential. Their transcriptional and epigenetic landscapes defined by RNA-seq and ATAC-seq identified the underlying gene regulatory networks, transcription factors and signalling pathways that control these different EMT transition states. Finally, these tumour subpopulations are localized in different niches that differentially regulateEMT transition states.

ORGANISM(S): Mus musculus

PROVIDER: GSE110584 | GEO | 2018/02/15

REPOSITORIES: GEO

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Project description:Metastasis consists of sequential steps initiated by cancer cells invading from the primary tumor site into neighboring tissues, followed by entry into the circulatory system and completed by extravasation and growth in distal organs. Circulating tumor cells, thus, encounter and adapt to multiple environmental changes during this transition. Epithelial-to-mesenchymal transition (EMT) is a developmental program that consists of loss of epithelial features concomitant with acquisition of mesenchymal features. Activation of EMT in cancer facilitates acquisition of aggressive traits and cancer invasion. EMT plasticity (EMP), the dynamic transition between multiple hybrid states in which cancer cells display both epithelial and mesenchymal phenotypes, confers survival advantages for cancer cells in the constantly changing environment. Therefore, understanding the molecular mechanisms regulating intermediate phenotypic states along the E–M spectrum is critical. Core EMT transcription factors (EMT-TFs), ZEB, SNAI and TWIST families, play an important role in EMT and its plasticity. In the present study we characterize FLASH as a regulator of EMP and multiple EMT-TFs. We demonstrate that loss of FLASH gives rise to a hybrid E/M phenotype with high epithelial scores even in the presence of TGFβ, as determined by computational methods using expression of predetermined sets of epithelial and mesenchymal genes. We demonstrate that FLASH is regulating expression of multiple cell junction proteins with an established role in cancer progression and that its role in EMT is independent of its histone biogenesis role. Further, we show that FLASH expression in cancer lines is inversely correlated with the epithelial score, consistent with its function as a repressor of the epithelial phenotype. Nonetheless, activation of a distinct set of mesenchymal markers concomitant with epithelial markers reveals the complex role of FLASH in EMT and indicates that intermediate E/M states could arise from opposing control by FLASH on different families of EMT-TFs.

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Identification of the tumour transition states occurring during EMT [ATAC-seq]

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