Abstract
BackgroundMetabolic changes in tumour cells are used in clinical imaging and may provide potential therapeutic targets. Human papillomavirus (HPV) status is important in classifying head and neck cancers (HNSCC), identifying a distinct clinical phenotype; metabolic differences between these HNSCC subtypes remain poorly understood.MethodsWe used RNA sequencing to classify the metabolic expression profiles of HPV+ve and HPV−ve HNSCC, performed a meta-analysis on FDG-PET imaging characteristics and correlated results with in vitro extracellular flux analysis of HPV−ve and HPV+ve HNSCC cell lines. The monocarboxylic acid transporter-1 (MCT1) was identified as a potential metabolic target and tested in functional assays.ResultsSpecific metabolic profiles were associated with HPV status, not limited to carbohydrate metabolism. There was dominance of all energy pathways in HPV-negative disease, with elevated expression of genes associated with glycolysis and oxidative phosphorylation. In vitro analysis confirmed comparative increased rates of oxidative phosphorylation and glycolysis in HPV-negative cell lines. PET SUV(max) scores however were unable to reliably differentiate between HPV-positive and HPV-negative tumours. MCT1 expression was significantly increased in HPV-negative tumours, and inhibition suppressed tumour cell invasion, colony formation and promoted radiosensitivity.ConclusionHPV-positive and negative HNSCC have different metabolic profiles which may have potential therapeutic applications.
Highlights
The identification of common links between oncogenes and important regulators of metabolism has fuelled a resurgent interest in cancer cell metabolism, despite the Warburg effect being first described nearly a century ago.[1]
Head and neck squamous cell carcinoma (HNSCC) has high rates of glucose uptake,[32] and FDG uptake in positron emission tomography (PET) imaging reflects this,[33] it is not clear whether metabolic differences exist between Human papillomavirus (HPV)+ve and HPV-ve HNSCC, tumour subgroups that show very different clinical behaviours
We found that human papillomavirus-negative (HPV−ve) tumours have a more glycolytic phenotype compared to their HPV+ve counterparts, and have a globally altered metabolic profile consistent with the greater requirements for macromolecule production, as well as alterations in other metabolic and biosynthetic pathways
Summary
The identification of common links between oncogenes and important regulators of metabolism has fuelled a resurgent interest in cancer cell metabolism, despite the Warburg effect being first described nearly a century ago.[1]. Head and neck squamous cell carcinoma (HNSCC) is currently classified into human papillomavirus-negative (HPV−ve) and -positive (HPV+ve) disease. There is increasing evidence of fundamental links between a tumour’s metabolic phenotype, its interactions with the tumour microenvironment and clinical outcome,[9,10,11,12] suggesting that specific metabolic pathways may promote tumour progression and represent therapeutic targets. Metabolic changes in tumour cells are used in clinical imaging and may provide potential therapeutic targets. Human papillomavirus (HPV) status is important in classifying head and neck cancers (HNSCC), identifying a distinct clinical phenotype; metabolic differences between these HNSCC subtypes remain poorly understood. METHODS: We used RNA sequencing to classify the metabolic expression profiles of HPV+ve and HPV−ve HNSCC, performed a meta-analysis on FDG-PET imaging characteristics and correlated results with in vitro extracellular flux analysis of HPV−ve and HPV+ve HNSCC cell lines. CONCLUSION: HPV-positive and negative HNSCC have different metabolic profiles which may have potential therapeutic applications
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