title: Development of the Theta Comparative Cell Scoring Method to Quantify Diverse Phenotypic Responses Between Distinct Cell Types.
abstract: In this article, we have developed novel data visualization tools and a Theta comparative cell scoring (TCCS) method, which supports high-throughput in vitro pharmacogenomic studies across diverse cellular phenotypes measured by multiparametric high-content analysis. The TCCS method provides a univariate descriptor of divergent compound-induced phenotypic responses between distinct cell types, which can be used for correlation with genetic, epigenetic, and proteomic datasets to support the identification of biomarkers and further elucidate drug mechanism-of-action. Application of these methods to compound profiling across high-content assays incorporating well-characterized cells representing known molecular subtypes of disease supports the development of personalized healthcare strategies without prior knowledge of a drug target. We present proof-of-principle data quantifying distinct phenotypic response between eight breast cancer cells representing four disease subclasses. Application of the TCCS method together with new advances in next-generation sequencing, induced pluripotent stem cell technology, gene editing, and high-content phenotypic screening are well placed to advance the identification of predictive biomarkers and personalized medicine approaches across a broader range of disease types and therapeutic classes.
authors.affiliation: Institute of Genetics and Molecular Medicine, Cancer Research UK Edinburgh Centre, University of Edinburgh , Edinburgh, United Kingdom .
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Warchal
authors.affiliation: Institute of Genetics and Molecular Medicine, Cancer Research UK Edinburgh Centre, University of Edinburgh , Edinburgh, United Kingdom .
authors.forename: John C
authors.initials: JC
authors.lastname: Dawson
authors.affiliation: Institute of Genetics and Molecular Medicine, Cancer Research UK Edinburgh Centre, University of Edinburgh , Edinburgh, United Kingdom .
authors.forename: Neil O
authors.initials: NO
authors.lastname: Carragher
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D061986:MCF-7 Cells; D010641:Phenotype; D013194:Staining and Labeling / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents