Doctor of Philosophy
Microbiology and Immunology
Mymryk, Joe S.
Viruses are the etiological agents of approximately 12% of human cancers. However, only a subset of viral infections eventually progress to cancer. As obligate intracellular parasites, viruses create a host-cell environment that is amenable to virus replication. These changes to host-cell processes during infection are enacted by virally-encoded proteins that act as molecular hubs. When these processes intersect with pathways that encourage the development of cancer, such as the p53 tumour suppressor pathway, these virally-encoded molecular hub proteins function as viral oncoproteins. One major requirement of both virus infected cells and rapidly growing cancer cells is an altered metabolism that provides the rapid production of energy and macromolecules required for either viral or cellular replication. Typically, this metabolic phenotype involves an increased rate of glycolysis and a decreased rate of cellular respiration despite the presence of ample oxygen that would otherwise encourage respiration. The purpose of this thesis is to investigate how viruses belonging to a subset viruses known as DNA tumour viruses can reprogram cellular metabolism. We hypothesize that DNA tumour viruses cause a cancer-like metabolic phenotype in the infected cell or cancerous tissue, which is similar to, but still distinct from, the metabolic phenotype in corresponding non-virally induced cancers. First, we determined that the 13S isoform of the E1A oncoprotein found in human adenovirus is responsible for causing an increase in glycolysis both as an endogenously expressed protein and in HAdV infected cells. Next, we utilized The Cancer Genome Atlas, a repository of patient tumour data, to determine that human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma (HNSCC) have a distinct metabolism-related transcriptome when compared to HPV- HNSCC, and that some of these metabolic genes are associated with patient survival. Finally, we confirm that DNA tumour virus-induced cancers do have a distinct metabolism-related transcriptome in the context of another cancer, Epstein-Barr virus associated gastric cancer. These findings highlight that the metabolic phenotypes of virally infected cells and cancer cells, while superficially similar, are distinct enough to represent potential novel druggable targets or biomarkers.
Summary for Lay Audience
In rare cases, cancer can develop from infections caused by certain viruses. Even before a virus causes cancer in an infected cell, the metabolism of the infected cell begins to resemble that of a cancer cell. Specifically, how that cell produces energy and what molecules it produces as building blocks for the production of new virus are very similar to the ways in which a cancer cell performs the same tasks to grow. The purpose of this thesis is to compare the metabolism of virus-infected cells and cancers to the metabolism of those that are not caused by a virus. The three viruses I discuss in this thesis are human adenovirus, human papillomavirus and Epstein-Barr virus. Human adenovirus does not cause cancers in humans, but it can cause cancers in rodent cells. Human adenovirus is frequently used to study how virus-induced cancer proceeds in cells. In the first part of my thesis, I explore how one of the tools used by human adenovirus, a viral protein called E1A, changes the metabolism of an infected cell to resemble that of cancer. Adenovirus can produce different versions of E1A. We identified that one version, 13S, is responsible for increasing cellular sugar consumption, a process known as glycolysis, both by itself and as part of a whole virus. Next we wanted to determine whether human cancers caused by viruses used different metabolic processes than similar non-viral cancers. The first cancer we examined was head and neck cancer caused by human papillomavirus (HPV). We used a database of patient tumours called The Cancer Genome Atlas, which contains information about the genetic messages (mRNA) produced by a cancer that codes for the cellular machines (enzymes) responsible for metabolism in the cancer. We found that head and neck cancer caused by HPV had a different set of messages than the same cancer that was not caused by the virus. We also found that the levels of these messages within HPV- induced head and neck cancers appeared to correlate with, but not necessarily cause, differences in patient survival. We performed a similar analysis for stomach cancers that were caused by Epstein-Barr virus. Once again, it appeared that the Epstein-Barr virus containing cancers had a different set of messages for metabolism-related enzymes than other stomach cancers. In conclusion, my thesis shows that cancers caused by viruses might produce energy and molecular building blocks in a way that differs from non-viral cancers. This could have implications for the treatment of cancers caused by viruses.
Prusinkiewicz, Martin, "Metabolic Reprogramming By DNA Tumour Viruses" (2021). Electronic Thesis and Dissertation Repository. 7667.
Creative Commons License
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Supplementary Table 1.1 - Metabolite Changes
Supplementary Table 1.2 - Metabolism Genes and Proteins.xlsx (10 kB)
Supplementary Table 1.2 - Metabolism Genes and Proteins
Supplementary Table 2.1 - Primer List.xlsx (10 kB)
Supplementary Table 2.1 - Primer List
Supplementary Table 3.1 - Metabolic Pathway Gene Expression.xlsx (88 kB)
Supplementary Table 3.1 - Metabolic Pathway Gene Expression
Supplementary Table 3.2 - Survival Curve Statistics.xlsx (38 kB)
Supplementary Table 3.2 - Survival Curve Statistics
Supplementary Table 4.1 - GC Metabolism Gene Expression.xlsx (74 kB)
Supplementary Table 4.1 - GC Metabolism Gene Expression