Model-based unsupervised learning informs metformin-induced cell-migration inhibition through an AMPK-independent mechanism in breast cancer
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Arjun P. Athreya1,*, Krishna R. Kalari2,*, Junmei Cairns3,*, Alan J. Gaglio4, Quin F. Wills5,7, Nifang Niu6, Richard Weinshilboum3, Ravishankar K. Iyer1, Liewei Wang3
1Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Champaign, IL, USA
2Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
3Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
4Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Champaign, IL, USA
5Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
6Department of Pathology, University of Chicago, Chicago, IL, USA
7Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
*These authors contributed equally to this work
Liewei Wang, email: email@example.com.
Ravishankar K. Iyer, email: firstname.lastname@example.org
Keywords: single cell, RNA-seq, breast cancer, metformin, unsupervised learning
Received: November 10, 2016 Accepted: February 18, 2017 Published: March 10, 2017
We demonstrate that model-based unsupervised learning can uniquely discriminate single-cell subpopulations by their gene expression distributions, which in turn allow us to identify specific genes for focused functional studies. This method was applied to MDA-MB-231 breast cancer cells treated with the antidiabetic drug metformin, which is being repurposed for treatment of triple-negative breast cancer. Unsupervised learning identified a cluster of metformin-treated cells characterized by a significant suppression of 230 genes (p-value < 2E-16). This analysis corroborates known studies of metformin action: a) pathway analysis indicated known mechanisms related to metformin action, including the citric acid (TCA) cycle, oxidative phosphorylation, and mitochondrial dysfunction (p-value < 1E-9); b) 70% of these 230 genes were functionally implicated in metformin response; c) among remaining lesser functionally-studied genes for metformin-response was CDC42, down-regulated in breast cancer treated with metformin. However, CDC42’s mechanisms in metformin response remained unclear. Our functional studies showed that CDC42 was involved in metformin-induced inhibition of cell proliferation and cell migration mediated through an AMPK-independent mechanism. Our results points to 230 genes that might serve as metformin response signatures, which needs to be tested in patients treated with metformin and, further investigation of CDC42 and AMPK-independence’s role in metformin's anticancer mechanisms.
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