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Modeling drug efficacy in the tumour microenvironment with Saccharomyces cerevisiae genome-wide screens in hypoxic conditions Tran, Grant

Abstract

Hypoxia, the state of reduced oxygen, is a microenvironment found in many solid tumours and is correlated with an increased risk in patient mortality. This is due to an increase in resistance to radiotherapy and chemotherapy as well as a decrease in drug efficacy. The mechanisms and cellular factors (gene products) associated with this reduced chemotherapeutic efficacy in hypoxia remains unclear. This research looks to identify cellular processes and pathways that cancerous cells are able to exploit in order to survive and thrive in this microenvironment. The eukaryotic model baker’s yeast Saccharomyces cerevisiae combined with a genome-wide approach was used to screen the yeast knockout collection for specific genotypes that are sensitive to the hypoxic environment alone, and in combination with commonly used chemotherapeutics. Pathways and processes identified in these screens include transcriptional regulation, cytoskeleton maintenance, ribosomal biogenesis, macromolecular complex assembly and the heat shock response. The combination of heat and hypoxia was found to result in a synergistic effect that drastically affected cell fitness. DNA-damaging chemotherapeutics screened in hypoxic conditions showed reduced efficacy. Genotypes most sensitive to drugs in the hypoxic environment fall into Gene Ontology (GO) terms categorized in the response to the specific mechanism of the drug. This includes DNA repair processes such as homologous repair, post-replicative repair and mismatch repair. The mechanistic specificity uncovered in these screens suggests that the hypoxic environment exacerbates drug-specific stresses, and the identified genotypes highlight gene products and pathways critical for these responses. Cell survival and success in this microenvironment therefore requires adaptations to these exacerbated stresses, a phenomenon successfully accomplished by resistant tumour cells. This research contributes to our understanding of cellular biology under this cancer microenvironment, and provides data to highlight the challenges in using chemotherapeutics to treat tumours.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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