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Cell. 2015 Feb 12;160(4):771-784. doi: 10.1016/j.cell.2015.01.026.

Targeting the adaptability of heterogeneous aneuploids.

Author information

1
Stowers Institute for Medical Research, 1000 East 50(th) Street, Kansas City, MO 64110, USA; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
2
Stowers Institute for Medical Research, 1000 East 50(th) Street, Kansas City, MO 64110, USA; Sorbonne Universités, UPMC Univ Paris 06, UMR 7238, Biologie Computationnelle et Quantitative, F-75005 Paris, France.
3
Stowers Institute for Medical Research, 1000 East 50(th) Street, Kansas City, MO 64110, USA.
4
Department of Molecular Microbiology and Biotechnology, George Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel.
5
Stowers Institute for Medical Research, 1000 East 50(th) Street, Kansas City, MO 64110, USA; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. Electronic address: rli@stowers.org.

Abstract

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.

PMID:
25679766
PMCID:
PMC4328141
DOI:
10.1016/j.cell.2015.01.026
[Indexed for MEDLINE]
Free PMC Article

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