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Background: Next generation sequencing has led to the categorization of thyroid cancer (TC) based on the molecular and transcriptomic profile into the BRAF-like and RAS-like tumors. The BRAF-RAS score (BRS) has been developed to quantify the extent to which the gene expression profile resembles either the BRAFV600E- or RAS-mutant profiles and is utilized as a continuous measure from -1 to +1, respectively. Oncogene-driven signaling pathways have an impact on the intracellular metabolism– glycolysis and oxidative phosphorylation (OXPHOS). There are limited data on the genotype-metabolic phenotype correlation in TC cells. Therefore, the goal of this study was to perform a comprehensive analysis of the association between the BRS and TC cell metabolism. Methods: We analyzed the mRNA expression of key enzymes involved in glycolysis (lactate dehydrogenase LDHA) and OXPHOS (ATP synthase) in 496 BRAF-like and RAS-like human TC tissue samples based on The Cancer Genome Atlas. We performed an in vitro study using 8 TC cell lines– 4 BRAF-like with BRS between -1 and 0, and 4 RAS-like with BRS between 0 and +1. OXPHOS was determined by measuring oxygen consumption rate (OCR) of each cell line using Seahorse XF Cell Mito Stress Test Kit, while Seahorse XF Glycolysis Stress Test Kit was used to measure the extracellular acidification rate (ECAR) due to anaerobic glycolysis The association between the OCR, ECAR and BRS was tested using the Pearson correlation coefficient (r). Student T-test was used to compare the continuous variables between the groups with a p-value of ≤ 0.05 as statistically significant. Results:RAS-like tumors were associated with higher mRNA expression of the OXPHOS marker ATP synthase than BRAF-like lesions, as evidenced by a moderate positive correlation (r = 0.5) between ATP synthase expression and BRS. BRAF-like tumors were characterized by a relatively higher mRNA expression of a glycolytic enzyme LDHA, as documented by a moderate negative correlation (r = -0.6) between LDHA expression and BRS. Consistently, functional in vitro studies revealed that RAS-like cell lines had a higher OXPHOS compared with BRAF-like cell lines (maximum OCR: 2538.4±1601.3 vs 548.5±276.5, p=0.049, respectively). The glycolysis rate was comparable between RAS-like and BRAF-like cell lines (maximum ECAR: 1290.4±520.5 vs 2399.9±1413.1, p=0.19, respectively). There was a strong positive correlation between the BRS and OCR (r=0.78) and a low to negligible negative correlation between BRS and ECAR (r=-0.26) in examined TC cell lines. Conclusions:BRAF-like and RAS-like tumors are characterized by distinct metabolic phenotypes with RAS-like TC more likely to utilize OXPHOS to meet metabolic demands. Therapeutic strategies targeting oncogene-driven signaling pathways and cancer metabolism based on distinct metabolic phenotypes may provide an individualized approach to TC therapy.

BRAF-Like and RAS-Like Thyroid Cancer is Characterized by Distinct Metabolic Phenotypes