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

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Thyroid cancer (TC) is associated with activating mutations in BRAF or RAS that led to its categorization into the BRAF-like or RAS-like tumors. Based on transcriptomic, metabolomic, and imaging analysis of two TC cohorts (TCGA; n = 496 and clinicaltrials.gov-NCT00001160; n = 101) we showed that RAS-like TC is more differentiated than BRAF-like, has a higher expression of sodium-iodide symporter necessary for radioiodine-uptake, a lower carbohydrate binding/uptake capacity and lower glucose uptake evidenced by 18Fluoro-Deoxy-Glucose positron emission tomography, but utilizes glucose via more energetically efficient Krebs cycle to meet its growth metabolic demands. Our in vitro models showed that oxidative phosphorylation in RAS-like TC is promoted by mTOR signaling, while glycolysis in BRAF-like tumors is associated with MEK/ERK signaling. Our study demonstrates that distinct metabolic phenotypes of TC affect the performance of radioiodine- or 18Fluoro-Deoxy-Glucose-based functional imaging and that targeting mTOR alters glucose metabolism and growth of RAS-like TC. We also found that metabolic plasticity and epithelial-to-mesenchymal transition (EMT) play a role in thyroid cancer resistance to standard treatment with lenvatinib. Exploration of mechanisms activating metabolic pathways and EMT transition in thyroid cancer may form a basis for targeted therapies aimed at overcoming lenvatinib resistance.