Abstract
Aneuploidy is common both in tumor cells responding to chemotherapeutic agents and in fungal cells adapting to antifungal drugs. Because aneuploidy simultaneously affects many genes, it has the potential to confer multiple phenotypes to the same cells. Here, we analyzed the mechanisms by which Candida albicans, the most prevalent human fungal pathogen, acquires the ability to survive both chemotherapeutic agents and antifungal drugs. Strikingly, adaptation to both types of drugs was accompanied by the acquisition of specific whole-chromosome aneuploidies, with some aneuploid karyotypes recovered independently and repeatedly from very different drug conditions. Specifically, strains selected for survival in hydroxyurea, an anticancer drug, acquired cross-adaptation to caspofungin, a first-line antifungal drug, and both acquired traits were attributable to trisomy of the same chromosome: loss of trisomy was accompanied by loss of adaptation to both drugs. Mechanistically, aneuploidy simultaneously altered the copy number of most genes on chromosome 2, yet survival in hydroxyurea or caspofungin required different genes and stress response pathways. Similarly, chromosome 5 monosomy conferred increased tolerance to both fluconazole and to caspofungin, antifungals with different mechanisms of action. Thus, the potential for cross-adaptation is not a feature of aneuploidy per se; rather, it is dependent on specific genes harbored on given aneuploid chromosomes. Furthermore, pre-exposure to hydroxyurea increased the frequency of appearance of caspofungin survivors, and hydroxyurea-adapted C. albicans cells were refractory to antifungal drug treatment in a mouse model of systemic candidiasis. This highlights the potential clinical consequences for the management of cancer chemotherapy patients at risk of fungal infections.
Highlights
The increased risk of opportunistic infections is of particular concern for cancer patients undergoing chemotherapy, because of the immunosuppression that accompanies it (Teoh and Pavelka 2016)
We find that adaptation of C. albicans to both chemotherapeutic and antifungal compounds is largely attributable to the acquisition of specific whole-chromosome aneuploidies and that genes on the aneuploid chromosome required for survival under hydroxyurea (HU) are not required for survival in caspofungin (CSP)
Aneuploidy Is Associated with Rapid Adaptation to Anticancer Drugs To determine the susceptibility of C. albicans laboratory strain SC5314 to chemotherapeutic drugs, we measured its ability to grow in the presence of different antimitotic, antimetabolite, or DNA-damaging agents used for cancer chemotherapy
Summary
The increased risk of opportunistic infections is of particular concern for cancer patients undergoing chemotherapy, because of the immunosuppression that accompanies it (Teoh and Pavelka 2016). Eukaryotic cells adapt to a broad range of stresses, with a classic example being the rapid adaptation of yeast cells to antifungal therapies (Cowen and Lindquist 2005; Bennett et al 2014; Berman 2016). This is of great clinical relevance: The rapid development of resistance to fungistatic drugs such as fluconazole (FLC) is well documented for both Candida glabrata and C. albicans (Borst et al 2005; Berkow and Lockhart 2017).
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