Targeting the adaptability of heterogeneous aneuploidy population

Abstract

Aneuploid genomes, characterized by unbalanced and diverse chromosome stoichiometry (karyotype), are associated with cancer malignancy and drug-resistance of human pathogenic fungi. My PhD projects studied three aspects of aneuploidy that are logically linked to each other: the production of aneuploidy by environmental stress; the impact of the heterogeneous aneuploidy population generated by stress on adaptability; the potential therapeutic strategy towards these heterogeneous aneuploidy populations with high adaptability, a root for the clinical challenge in treating aneuploidy diseases such as cancer. We investigated whether pleiotropic stress could induce the production of aneuploidy in budding yeast. We showed that while diverse stresses can induce an increase in chromosome instability (CIN), proteotoxic stress, caused by transient Hsp90 inhibition or heat-shock, drastically elevated CIN to produce karyotypically mosaic cell population. The latter effect is linked to an evolutionarily conserved role for Hsp90 chaperon complexes in kinetochore assembly. We found the induction of aneuploidy population potentiates adaptability. Continued growth in the presence of Hsp90 inhibitor resulted in emergence of drug-resistant colonies with chromosome XV gain. This drug-resistance phenotype is a quantitative trait involving copy number increases of at least two genes located on chromosome XV. Short-term exposure to Hsp90 stress, which produced an aneuploidy population with heterogeneous karyotypes, potentiated fast adaptation to unrelated cyto-toxic compounds through different aneuploid chromosome stoichiometries. We designed an evolutionary trap to harness the adaptability of heterogeneous aneuploidy populations with high adaptability. Using a combination of experimental data and a general statistical model, we showed that the degree of phenotypic variation, thus evolvability, escalates with the degree of overall growth suppression irrespective of stress mechanisms. Such scaling explains the challenge of treating aneuploidy diseases with diverse different karyotypes by imposing a single mode of inhibition, yet specific karyotype features can be highly targetable. Motivated by this finding, we proposed an "evolutionary trap" targeting both karyotypic diversity and fitness of the population. This strategy entails a selective condition "channeling" a karyotypically divergent population into one with a predominant and drugable karyotypic feature. We provided a proof-of-principle test with mechanistic explanation in budding yeast and demonstrated the potential efficacy of this strategy toward aneuploidy-based azole resistance in the human pathogen Candida albicans. Karyotype channeling also happens naturally in tumors, which is resulted from adaptation to the tissue micro-environment and/or the need for oncogenic transformation. This natural karyotypic selection may be leveraged by drug treatment targeting the selected karyotype feature. Thus, the strategy proposed here may be utilized for designing a class of treatment regime distinct from current therapies.