Snail knockdown reverses stemness and inhibits tumour growth in ovarian cancer

Abstract

To develop effective therapies for advanced high grade serous ovarian cancer (HGSOC), understanding mechanisms of recurrence and metastasis is necessary. In this study, we define the epithelial/mesenchymal status of cell lines that accurately model HGSOC, and evaluate the therapeutic potential of targeting Snai1 (Snail), a master regulator of the epithelial/mesenchymal transition (EMT) in vitro and in vivo. The ratio of Snail to E-cadherin (S/E index) at RNA and protein levels was correlated with mesenchymal morphology in four cell lines. The cell lines with high S/E index (OVCAR8 and COV318) showed more CSC-like, motile, and chemoresistant phenotypes than those with low S/E index (OVSAHO and Kuramochi). We tested the role of Snail in regulation of malignant phenotypes including stemness, cell motility, and chemotherapy resistance: shRNA-mediated knockdown of Snail reversed these malignant phenotypes. Interestingly, the expression of let-7 tumour suppressor miRNA was upregulated in Snail knockdown cells. Furthermore, knockdown of Snail decreased tumour burden in an orthotopic xenograft mouse model. We conclude that Snail is important in controlling HGSOC malignant phenotypes and suggest that the Snail/Let-7 axis may be an attractive target for HGSOC treatment.

A mechanism-based computational model to capture the interconnections among epithelial-mesenchymal transition, cancer stem cells and Notch-Jagged signaling

“…This prediction is supported by our analysis of gene expression profiles of CSCs belonging to different cancer subtypes, and report the presence of epithelial, hybrid E/M and mesenchymal CSCs. Recent experimental studies have identified such heterogeneity in EMT status of different CSCs across cancer subtypes [ 10 , 12 , 35 , 54 – 59 ], supporting the idea about a dynamic ‘stemness window’ [ 13 ] along the ‘EMT axis’. Moreover, a recent clinical study identified different subsets of CTCs - those that expressed EMT markers but not stemness ones, those that expressed stemness markers but not EMT, those that expressed both EMT and stemness markers, and those that expressed neither.…”

NRF2 activates a partial Epithelial-Mesenchymal Transition and is maximally present in a hybrid Epithelial/Mesenchymal phenotype

“…Our earlier efforts at quantifying the association between EMT and stemness have predicted that cells in hybrid E/M states are more inclined to gain stem-like properties [27,42,43], a prediction that has been recently validated in vitro and in vivo [2, 44,45]. Reinforcing these predictions, NRF2 has been related to cancer stem-like traits and chemo-resistance [35].…”

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

“…Numerous studies in a variety of tissue types have also found EMT-TFs, namely SNAIL1/2, ZEB1/2 and TWIST, to directly confer drug-resistance in cancer [70][71][72][73][74][75][76][77][78][79][80][81] , as summarised in Table 2. Upregulation of these transcription factors alone can be sufficient to confer drug resistance [71,75] . ZEB1 is highly expressed in glioblastoma cells, where a ZEB1-miR200 feedback loop connects this with a number of downstream targets (ROBO1, c-MYB and MGMT), and increased levels of this EMT-TF are associated with both drug resistance and reduced survival [79] .…”