HPV, tumour metabolism and novel target identification in head and neck squamous cell carcinoma

Abstract

Background 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. The monocarboxylic acid transporter-1 (MCT1) was identified as a potential metabolic target and tested in functional assays. Results Specific 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. Conclusion HPV-positive and negative HNSCC have different metabolic profiles which may have potential therapeutic applications.

Usefulness of Hybrid PET/MRI in Clinical Evaluation of Head and Neck Cancer Patients

“…In the present study, differences between SUVmax or SUVmean and HPV or p16 presence were insignificant. Comparable results have been obtained in other studies, where no differences in SUVmax values between p16-and HPV-positive, and p16-and HPV-negative patients were reported [40][41][42]. By contrast, Schouten et al demonstrated that SUVmax in HPV-positive tumors was significantly lower than in HPV-negative tumors [43].…”

Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers

“…Previous studies indicate that HPV+ HNSCC is more reliant on oxidative phosphorylation as an energy source than HPV-HNSCC [15]. Oxidative phosphorylation requires electron transport via mitochondrial cellular respiratory complexes I-IV [17].…”

“…Increased expression of the monocarboxylic acid transporter family member, SLC16A1 (MCT1) was recently reported to be associated with poor survival outcomes in HNSCC [15]. Although, expression of SLC16A1 was significantly higher than normal head and neck tissues for both HPV+ and HPV-HNSCC, and expression of SLC16A1 was higher in HPV-HNSCC than HPV+ HNSCC, the impact of differential expression of SLC16A1 on overall survival in either HPV+ or HPV-HNSCC was not significant (p > 0.05).…”

“…These 229 genes were manually selected ( Supplementary Table S1) as they are involved in eight central cellular metabolic pathways or processes, of which cellular respiration was then separated into its respective complexes. The number of genes examined from each pathway was as follows: glycolysis, 36 genes (adapted from GO:0061621 and [55]); TCA cycle, 20 genes (adapted from GO:0006099 and [56]); mitochondrial respiratory complex I, 43 genes (adapted from GO:0045333, GO:0046043 and [57]); mitochondrial respiratory complex II, 4 genes (adapted from GO:0045333, GO:0046043 and [58]); mitochondrial respiratory complex III, 9 genes (adapted from GO:0045333, GO:0046043 and [59,60]); mitochondrial respiratory complex IV, 31 genes (adapted from GO:0045333, GO:0046043 and [61]); mitochondrial ATPase, 16 genes (adapted from GO:0046043 and [62]); fatty acid synthesis, 21 genes (adapted from GO:0019368, GO:0046949, GO: 0006629 and [63][64][65][66]); β-oxidation, 18 genes (adapted from GO:0003995, GO:0003985, GO: 0004300 and [67]); glutaminolysis, 7 genes (adapted from GO:0004069, GO:0004352, GO: 0004359, GO: 0004021 and [68]); pentose phosphate pathway, 11 genes (GO:0006098 and [69]); monocarboxylic acid transport (MCT) family, 13 genes (adapted from GO:0008028 and [15]). Boxplot comparisons of gene expression were made with GraphPad Prism v7.0 (Graphpad Software, Inc., San Diego, California, USA).…”

“…These changes can include similar tumour-associated metabolic changes as described above. Infection with HPV has been shown to phenocopy cancer-like metabolic changes that are maintained in HPV+ HNSCC [15]. Examination of how the metabolic phenotype differs between HPV+ and HPV-HNSCC could lead to the identification of targetable metabolic changes and potential new treatment options that are specific for either HPV+ HNSCCs or HPV-HNSCCs.…”