Whole-genome multiparametric screening to identify modulators of epithelial-to-mesenchymal transition

Said, Nur Akmarina B.M., Gould, Cathryn M., Lackovic, Kurt, Simpson, Kaylene J., & Williams, Elizabeth D. (2014) Whole-genome multiparametric screening to identify modulators of epithelial-to-mesenchymal transition. ASSAY and Drug Development Technologies, 12(7), pp. 385-394.

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Abstract

Metastasis accounts for the poor prognosis of the majority of solid tumors. The phenotypic transition of nonmotile epithelial tumor cells to migratory and invasive “mesenchymal” cells (epithelial-to-mesenchymal transition [EMT]) enables the transit of cancer cells from the primary tumor to distant sites. There is no single marker of EMT; rather, multiple measures are required to define cell state. Thus, the multiparametric capability of high-content screening is ideally suited for the comprehensive analysis of EMT regulators. The aim of this study was to generate a platform to systematically identify functional modulators of tumor cell plasticity using the bladder cancer cell line TSU-Pr1-B1 as a model system. A platform enabling the quantification of key EMT characteristics, cell morphology and mesenchymal intermediate filament vimentin, was developed using the fluorescent whole-cell-tracking reagent CMFDA and a fluorescent promoter reporter construct, respectively. The functional effect of genome-wide modulation of protein-coding genes and miRNAs coupled with those of a collection of small-molecule kinase inhibitors on EMT was assessed using the Target Activation Bioapplication integrated in the Cellomics ArrayScan platform. Data from each of the three screens were integrated to identify a cohort of targets that were subsequently examined in a validation assay using siRNA duplexes. Identification of established regulators of EMT supports the utility of this screening approach and indicated capacity to identify novel regulators of this plasticity program. Pathway analysis coupled with interrogation of cancer-related expression profile databases and other EMT-related screens provided key evidence to prioritize further experimental investigation into the molecular regulators of EMT in cancer cells.

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ID Code: 77666
Item Type: Journal Article
Refereed: Yes
Keywords: Whole-genome, Multiparametric screening, prostate cancer, bladder cancer, epithelial to mesenchymal transition
DOI: 10.1089/adt.2014.593
ISSN: 1557-8127
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Cell Biology (111201)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Genetics (111203)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2014 Mary Ann Liebert, Inc.
Copyright Statement: This is a copy of an article published in ASSAY and Drug Development Technologies © 2014 Mary Ann Liebert, Inc.; ASSAY and Drug Development Technologies is available online at: http://online.liebertpub.com.
Deposited On: 14 Oct 2014 22:41
Last Modified: 15 Oct 2014 21:54

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