Targeting the adaptability of heterogeneous aneuploids. Cell 2015 Feb 12;160(4):771-784
Date
02/14/2015Pubmed ID
25679766Pubmed Central ID
PMC4328141DOI
10.1016/j.cell.2015.01.026Scopus ID
2-s2.0-84922718815 (requires institutional sign-in at Scopus site) 111 CitationsAbstract
Aneuploid genomes, characterized by unbalanced chromosome stoichiometry (karyotype), are associated with cancer malignancy and drug resistance of pathogenic fungi. The phenotypic diversity resulting from karyotypic diversity endows the cell population with superior adaptability. We show here, using a combination of experimental data and a general stochastic model, that the degree of phenotypic variation, thus evolvability, escalates with the degree of overall growth suppression. Such scaling likely explains the challenge of treating aneuploidy diseases with a single stress-inducing agent. Instead, we propose the design of an "evolutionary trap" (ET) targeting both karyotypic diversity and fitness. This strategy entails a selective condition "channeling" a karyotypically divergent population into one with a predominant and predictably drugable karyotypic feature. We provide a proof-of-principle case in budding yeast and demonstrate the potential efficacy of this strategy toward aneuploidy-based azole resistance in Candida albicans. By analyzing existing pharmacogenomics data, we propose the potential design of an ET against glioblastoma.
Author List
Chen G, Mulla WA, Kucharavy A, Tsai HJ, Rubinstein B, Conkright J, McCroskey S, Bradford WD, Weems L, Haug JS, Seidel CW, Berman J, Li RAuthor
Guangbo Chen PhD Assistant Professor in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AneuploidyAntifungal Agents
Antineoplastic Agents, Phytogenic
Camptothecin
Candida albicans
Cell Line, Tumor
Drug Resistance, Fungal
Drug Resistance, Neoplasm
ErbB Receptors
Fluconazole
Glioblastoma
Humans
Hygromycin B
Saccharomyces cerevisiae
