Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines

Cursons, Joseph; Leuchowius, Karl Johan; Waltham, Mark; Tomaskovic-Crook, Eva; Foroutan, Momeneh; Bracken, Cameron P.; Redfern, Andrew; Crampin, Edmund J.; Street, Ian P.; Davis, Melissa J.; Thompson, Erik W.

doi:10.1186/s12964-015-0106-x

Cited by 55 publications

(63 citation statements)

References 112 publications

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“…A SOX10-low state is associated with reduced cell proliferation and engagement of EMT-like processes in melanoma to promote more invasive phenotypes [55] - a state maintained, in part, through mutual-antagonism with the closely related transcription factor SOX9 [56]. SOX10 suppression contributes to BRAF- and/or MEK-inhibitor resistance in BRAF mutated melanoma, by activating TGFβ signalling to upregulate EGFR and PDGFRB [57], whilst increasing SOX9 transcript abundance has been observed in breast cancer EMT [58]. SOX9-high LM-MEL cell lines are also enriched for an invasive phenotype (Fig.…”

Section: Resultsmentioning

confidence: 99%

Systems analysis identifies miR-29b regulation of invasiveness in melanoma

et al. 2016

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BackgroundIn many cancers, microRNAs (miRs) contribute to metastatic progression by modulating phenotypic reprogramming processes such as epithelial-mesenchymal plasticity. This can be driven by miRs targeting multiple mRNA transcripts, inducing regulated changes across large sets of genes. The miR-target databases TargetScan and DIANA-microT predict putative relationships by examining sequence complementarity between miRs and mRNAs. However, it remains a challenge to identify which miR-mRNA interactions are active at endogenous expression levels, and of biological consequence.MethodsWe developed a workflow to integrate TargetScan and DIANA-microT predictions into the analysis of data-driven associations calculated from transcript abundance (RNASeq) data, specifically the mutual information and Pearson’s correlation metrics. We use this workflow to identify putative relationships of miR-mediated mRNA repression with strong support from both lines of evidence. Applying this approach systematically to a large, published collection of unique melanoma cell lines – the Ludwig Melbourne melanoma (LM-MEL) cell line panel – we identified putative miR-mRNA interactions that may contribute to invasiveness. This guided the selection of interactions of interest for further in vitro validation studies.ResultsSeveral miR-mRNA regulatory relationships supported by TargetScan and DIANA-microT demonstrated differential activity across cell lines of varying matrigel invasiveness. Strong negative statistical associations for these putative regulatory relationships were consistent with target mRNA inhibition by the miR, and suggest that differential activity of such miR-mRNA relationships contribute to differences in melanoma invasiveness. Many of these relationships were reflected across the skin cutaneous melanoma TCGA dataset, indicating that these observations also show graded activity across clinical samples. Several of these miRs are implicated in cancer progression (miR-211, -340, -125b, −221, and -29b). The specific role for miR-29b-3p in melanoma has not been well studied. We experimentally validated the predicted miR-29b-3p regulation of LAMC1 and PPIC and LASP1, and show that dysregulation of miR-29b-3p or these mRNA targets can influence cellular invasiveness in vitro.ConclusionsThis analytic strategy provides a comprehensive, systems-level approach to identify miR-mRNA regulation in high-throughput cancer data, identifies novel putative interactions with functional phenotypic relevance, and can be used to direct experimental resources for subsequent experimental validation.Computational scripts are available: http://github.com/uomsystemsbiology/LMMEL-miR-miner Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0554-y) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Systems analysis identifies miR-29b regulation of invasiveness in melanoma

et al. 2016

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“…is a widely used model for the study of EMT in breast cancer (Bonnomet et al, 2012;Cursons et al, 2015;Davis et al, 2014;Lo et al, 2007). The MDA-MB-468 cell line expresses high levels of the EGF receptor (EGFR) and is responsive to EMT induction by EGF, a growth factor present in the tumor microenvironment and associated with tumor progression (Goswami et al, 2005).…”

Section: Epidermal Growth Factor (Egf)-induced Emt In Basal-like Mda-mentioning

confidence: 99%

“…The MDA-MB-468 cell line expresses high levels of the EGF receptor (EGFR) and is responsive to EMT induction by EGF, a growth factor present in the tumor microenvironment and associated with tumor progression (Goswami et al, 2005). Various regulators of the EMT phenotype have been identified in MDA-MB-468 cells, including cell surface receptors (Lester et al, 2007) and components of intracellular signaling pathways (Cursons et al, 2015;Jo et al, 2009;Lo et al, 2007). Recently, the calcium permeable ion channel TRPM7 was identified as a regulator of the induction of the intermediate filament protein vimentin, a well-characterized mesenchymal marker, in the MDA-MB-468 model of EGF-induced EMT (Davis et al, 2014).…”

Section: Epidermal Growth Factor (Egf)-induced Emt In Basal-like Mda-mentioning

confidence: 99%

Janus kinases and Src family kinases in the regulation of EGF-induced vimentin expression in MDA-MB-468 breast cancer cells

Stewart

Azimi

Brooks

et al. 2016

The International Journal of Biochemistry & Cell Biology

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“…Hypoxic microenvironments may promote adaptive survival programs, which are often associated with resistance to apoptosis, angiogenesis and migration (Ruan et al., 2009). Recent studies show that hypoxia induces EMT in a variety of cancer cell types (Cannito et al., 2008; Cooke et al., 2012; Misra et al., 2012; Sahlgren et al., 2008; Salnikov et al., 2012; Shaikh et al., 2012; Zhang et al., 2013), including the MDA‐MB‐468 cell line used in our study (Cursons et al., 2015; Jo et al., 2009; Lundgren et al., 2009).…”

Section: Introductionmentioning

confidence: 99%

Altered purinergic receptor‐Ca²⁺ signaling associated with hypoxia‐induced epithelial‐mesenchymal transition in breast cancer cells

et al. 2015

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Hypoxia is a feature of the microenvironment of many cancers and can trigger epithelial-mesenchymal transition (EMT), a process by which cells acquire a more invasive phenotype with enriched survival. A remodeling of adenosine 5'-triphosphate (ATP)-induced Ca(2+) signaling via purinergic receptors is associated with epidermal growth factor (EGF)-induced EMT in MDA-MB-468 breast cancer cells. Here, we assessed ATP-mediated Ca(2+) signaling in a model of hypoxia-induced EMT in MDA-MB-468 cells. Like EGF, hypoxia treatment (1% O2) was also associated with a significant reduction in the sensitivity of MDA-MB-468 cells to ATP (EC50 of 0.5 μM for normoxic cells versus EC50 of 5.8 μM for hypoxic cells). Assessment of mRNA levels of a panel of P2X and P2Y purinergic receptors following hypoxia revealed a change in levels of a suite of purinergic receptors. P2X4, P2X5, P2X7, P2Y1 and P2Y11 mRNAs decreased with hypoxia, whereas P2Y6 mRNA increased. Up-regulation of P2Y6 was a common feature of both growth factor- and hypoxia-induced models of EMT. P2Y6 levels were also significantly increased in basal-like breast tumors compared to other subtypes and breast cancer patients with higher P2Y6 levels showed reduced overall survival rates. P2Y6 siRNA-mediated silencing and the P2Y6 pharmacological inhibitor MRS2578 reduced hypoxia-induced vimentin protein expression in MDA-MB-468 cells. P2Y6 inhibition also reduced the migration of mesenchymal-like MDA-MB-231 breast cancer cells. The up-regulation of P2Y6 appears to be a common feature of the mesenchymal phenotype of breast cancer cells and inhibition of this receptor may represent a novel therapeutic target in breast cancer metastasis.

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Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines

Cited by 55 publications

References 112 publications

Systems analysis identifies miR-29b regulation of invasiveness in melanoma

Systems analysis identifies miR-29b regulation of invasiveness in melanoma

Janus kinases and Src family kinases in the regulation of EGF-induced vimentin expression in MDA-MB-468 breast cancer cells

Altered purinergic receptor‐Ca²⁺ signaling associated with hypoxia‐induced epithelial‐mesenchymal transition in breast cancer cells

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Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines

Cited by 55 publications

References 112 publications

Systems analysis identifies miR-29b regulation of invasiveness in melanoma

Systems analysis identifies miR-29b regulation of invasiveness in melanoma

Janus kinases and Src family kinases in the regulation of EGF-induced vimentin expression in MDA-MB-468 breast cancer cells

Altered purinergic receptor‐Ca2+ signaling associated with hypoxia‐induced epithelial‐mesenchymal transition in breast cancer cells

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Altered purinergic receptor‐Ca²⁺ signaling associated with hypoxia‐induced epithelial‐mesenchymal transition in breast cancer cells