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 journalArticle

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
Externally publishedYes

Fingerprint

Aneuploidy
Azoles
Candida
Stochastic models
Chromosomes
Fungi
Stoichiometry
Yeast
Saccharomycetales
Genes
Pharmacogenetics
Cells
Glioblastoma
Candida albicans
Karyotype
Drug Resistance
Population
Neoplasms
Pharmaceutical Preparations
Genome

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Chen, G., Mulla, W. A., Kucharavy, A., Tsai, H. J., Rubinstein, B., Conkright, J., ... Li, R. (2015). Targeting the adaptability of heterogeneous aneuploids. Cell, 160(4), 771-784. https://doi.org/10.1016/j.cell.2015.01.026

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

In: Cell, Vol. 160, No. 4, 12.02.2015, p. 771-784.

Research output: Contribution to journalArticle

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, R 2015, 'Targeting the adaptability of heterogeneous aneuploids', Cell, vol. 160, no. 4, pp. 771-784. https://doi.org/10.1016/j.cell.2015.01.026
Chen G, Mulla WA, Kucharavy A, Tsai HJ, Rubinstein B, Conkright J et al. Targeting the adaptability of heterogeneous aneuploids. Cell. 2015 Feb 12;160(4):771-784. https://doi.org/10.1016/j.cell.2015.01.026
Chen, Guangbo ; Mulla, Wahid A. ; Kucharavy, Andrei ; Tsai, Hung Ji ; Rubinstein, Boris ; Conkright, Juliana ; McCroskey, Scott ; Bradford, William D. ; Weems, Lauren ; Haug, Jeff S. ; Seidel, Chris W. ; Berman, Judith ; Li, Rong. / Targeting the adaptability of heterogeneous aneuploids. In: Cell. 2015 ; Vol. 160, No. 4. pp. 771-784.
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