Glucose Utilization Differs Between RAS-like and BRAF-like Thyroid Cancer

Authors

• S Kumari
• E Chuki
• J Klubo-Gwiezdzinska

Abstract

Background: Thyroid cancer (TC) has been clustered based on its molecular signature and driver mutations- into RAS-like and BRAF-like. Given variable 18F-deoxyglucose Positron Emission Tomography (FDG-PET)-avidity, glucose metabolism may differ between RAS-like and BRAF-like TC. Methods: Based on IRB approved protocol, we obtained fresh frozen human TC samples with corresponding normal tissue, as well as 6 human TC cell lines and performed central carbon metabolism analysis using mass spectrometry. We analyzed mRNA expression of oxidative phosphorylation (OXPHOS) and glycolytic enzymes in 496 human TC tissue samples of The Cancer Genome Atlas. Standard BRAF-RAS score (BRS) was used to divide TC into BRAF-like (BRS -1 to 0) and RAS-like (BRS 0 to +1) using gene expression profile. OXPHOS was measured by oxygen consumption rate (OCR) using Seahorse XF Cell Mito Stress Assay. Results: The study consisted of 20 patients, 13 with BRAF-like and 7 with RAS-like TC, aged 43±12 years, 90% females. Metabolomics data revealed that RAS-like TC was characterized by significantly higher Krebs cycle activation (p<0.001) in comparison to BRAF-like tumors and cell lines. RAS-like cells had an upregulated OXPHOS in comparison to BRAF-like TC (p=0.004). Transcriptomic profiling of 496 TC samples revealed that RAS-like TC has an increased expression of tested OXPHOS enzymes compared to BRAF-like TC, p<0.001), while BRAF-like TC had upregulated glycolysis marker lactate dehydrogenase (p<0.001) Conclusions: RAS-like TC is more likely to utilize glucose through Krebs cycle, while BRAF-like TC utilizes anaerobic glycolysis, suggesting need for individualized therapeutic strategies.

Scientific Focus Area: Cancer Biology

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