Abstract
Using a data driven analysis of a high-content screen, we have uncovered new regulators of epithelial-to-mesenchymal transition (EMT) induced cell migration. Our results suggest that increased expression of miR614 can alter cell intrinsic gene expression to enhance single cell and collective migration in multiple contexts. Interestingly, miR614 specifically increased the expression of the EMT transcription factor Slug while not altering existing epithelial character or inducing other canonical EMT regulatory factors. Analysis of two different cell lines identified a set of genes whose expression is altered by the miR614 through direct and indirect mechanisms. Prioritization driven by functional testing of 25 of the miR614 suppressed genes uncovered the mitochondrial small GTPase Miro1 and the transmembrane protein TAPT1 as miR614 suppressed genes that inhibit migration. Notably, the suppression of either Miro1 or TAPT1 was sufficient to increase Slug expression and the rate of cell migration. Importantly, reduced TAPT1 expression correlated with an increased risk of relapse in breast cancer patients. Together, our results reveal how increased miR614 expression and the suppression of TAPT1 and Miro1 modulate the EMT state and migratory properties of breast cancer cells.
Highlights
The activation of epithelial-to-mesenchymal transition (EMT) programs confers tumor cells with the ability to invade [1]
EMTs are coordinated by transcription factors (EMT-TFs) that induce mesenchymal genes, such as the microfilament protein vimentin, extracellular matrix (ECM) targeting proteases and regulators of the cytoskeleton that enhance the rate of cell migration [6,7]
Our results reveal that miR614 and the suppression of Miro1 and TAPT1 potentiate Slug expression and EMT induced migration
Summary
The activation of epithelial-to-mesenchymal transition (EMT) programs confers tumor cells with the ability to invade [1]. These invasive cells have the potential to intravasate into blood and lymphatic vessels and disperse to new organs [2]. EMTs are coordinated by transcription factors (EMT-TFs) that induce mesenchymal genes, such as the microfilament protein vimentin, extracellular matrix (ECM) targeting proteases and regulators of the cytoskeleton that enhance the rate of cell migration [6,7]. EMT attributes influence migration rate and the relative ability of cells to reorganize the ECM [15]. There is variability in EMT programs, and this heterogeneity influences the invasive properties of tumor cells. Identifying regulatory programs that influence EMT induced invasion can improve prognostic measures and assist in specifying treatment options [16]
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