Targeting the adaptability of heterogeneous aneuploids

Guangbo Chen, Wahid A. Mulla, Andrei Kucharavy, Hung Ji Tsai, Boris Rubinstein, Juliana Conkright, Scott McCroskey, William D. Bradford, Lauren Weems, Jeff S. Haug, Chris W. Seidel, Judith Berman, Rong Li

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)771-784
Number of pages14
JournalCell
Volume160
Issue number4
DOIs
StatePublished - Feb 12 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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