Cross-talk between oncogene-driven signaling pathways and thyroid cancer metabolism

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Background: The next-generation sequencing led to the categorization of thyroid cancer (TC) into BRAF-like and RAS-like tumors. The BRAF-RAS score (BRS) was 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 intracellular metabolismglycolysis and oxidative phosphorylation (OXPHOS). There are limited data on the genotype-metabolic phenotype correlation in TC. Therefore, the goal of this study was to perform a comprehensive analysis of the association between BRS and TC metabolism. Methods: We analyzed mRNA expression of key enzymes involved in glycolysis and OXPHOS in 496 BRAF-like and RAS-like human TC tissue samples based on The Cancer Genome Atlas. We performed an in vitro study using 6 TC cell lines 4 BRAF-like, and 2 RAS-like. OXPHOS was determined by measuring oxygen consumption rate (OCR), while glycolysis was measured using the extracellular acidification rate (ECAR), utilizing the Seahorse XF analyzer. The association between the OCR, ECAR, and BRS was tested using the Pearson correlation coefficient r. Results: RAS-like tumors were associated with higher mRNA expression of OXPHOS-related genes, as documented by a low-to-moderate positive correlation between its mRNA expression and BRS - r ranging from 0.28, p<0.001 for SDHB to 0.54, p<0.001 for cytochrome bc1 complex. BRAF-like tumors were characterized by a higher expression of glycolytic enzymes as evidenced by a low-to-strong negative correlation between its mRNA expression and BRS - r ranging from -0.2 for hexokinase II to -0.65 for pyruvate kinase. Consistently, RAS-like cell lines were utilizing OXPHOS and glycolysis for energy production, while BRAF-like cell lines were characterized by a glycolytic phenotype and low OXPHOS rate. There was a strong positive correlation between the BRS and OCR (r=0.79, p=0.03) and no correlation between BRS and ECAR (r=-0.12, p=0.82). Conclusions: BRAF-like and RAS-like tumors are characterized by a distinct metabolic phenotype, with RAS-like tumors relying more on OXPHOS than BRAF-like cells. Therapeutic strategies targeting oncogene-driven signaling pathways and distinct cancer metabolism are necessary for the individualized approach to TC therapy.