PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
Combinatorial co-targeting by miRNAs: a subtle but strong regulator of epithelia-mesenchymal transitions
Joseph Cursons 1, , Katherine A Pillman 3, , Kaitlin G Scheer 3 , Philip A Gregory 3, , Momeneh Foroutan 1, , Soroor Hediyeh-Zadeh 1 , John Toubia 3 , Edmund J Crampin 6, , Gregory J Goodall 3, , Cameron P Bracken 3, & Melissa J Davis 1,
1Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; 2Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; 3Centre for Cancer Biology, an Alliance of SA Pathology and University of South Australia, North Terrace, Adelaide, SA 5000, Australia; 4Department of Medicine, University of Adelaide, Adelaide, SA 5005, Australia; 5The University of Melbourne, Department of Surgery, St. Vincent’s Hospital, Fitzroy, VIC 3065, Australia; 6Systems Biology Laboratory, University of Melbourne, Parkville, VIC 3010, Australia; 7ARC Centre of Excellence in Convergent Bio-Nano Science, Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia; 8School of Mathematics and Statistics, University of Melbourne, Parkville, VIC 3010, Australia; 9Department of Biochemistry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3010, Australia.
Epithelial-mesenchymal transition (EMT) and the reverse mesenchymal-epithelial transition (MET) are normal biological processes, however they are also thought to play a critical role in the progression and metastasis of cancers, including breast cancer. Cancer cells reactivate the gene expression programs of EMT and MET through a wide range of mechanisms, and better understanding of these regulatory processes will lead to the identification of therapeutically actionable targets. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, functioning in part by facilitating the degradation of target mRNA transcripts. MiRNAs have an established role in controlling EMT, and many studies have demonstrated the role of individual miRNAs using overexpression at levels greatly exceeding physiological abundance, which can in turn lead to off-target effects, and over-estimation of functional effects. Computationally, we place the TCGA breast cancer samples, and a collection of >60 breast cancer cell lines on a landscape defining epithelial and mesenchymal phenotypes, and use this as a tool to explore phenotypic transitions. Analysing a human mammary cell model of EMT with endogenous changes in miRNA expression, we found evidence that a set of miRNAs, including the miR-200 and miR-182/183 family members, cooperate in post-transcriptional regulation, both reinforcing and buffering transcriptional output. Investigating this, we demonstrate that combinatorial treatment could induce MET with miRNA concentrations much closer to endogenous levels and with less off-target effects. This discovery, that co-operative targeting by miRNAs is important for their physiological function, has opened the way for a more-refined understanding of post-transcriptional regulatory processes. Future work classifying miRNAs should consider such combinatorial effects, and combinatorial co-targeting represents a new strategy for tuning biological processes involved in cancer progression through small adjustments to this critical regulatory layer.
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Oncology Abstracts
ISSN 2631-4657 (online)
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