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

背景：下一代测序导致甲状腺癌（TC）分为BRAF样和RAS样肿瘤。开发BRAF-RAS评分（BRS）以定量基因表达谱与BRAFV 600 E-或RAS-突变谱相似的程度，并分别用作-1至+1的连续测量。癌基因驱动的信号通路对细胞内代谢有影响，如糖酵解和氧化磷酸化（OXPHOS）。关于TC的基因型-代谢表型相关性的数据有限。因此，本研究的目的是对BRS和TC代谢之间的关联进行全面分析。 研究方法：我们基于癌症基因组图谱分析了496例BRAF样和RAS样人TC组织样本中参与糖酵解和OXPHOS的关键酶的mRNA表达。我们使用6个TC细胞系4个BRAF样和2个RAS样进行了体外研究。OXPHOS通过测量氧消耗速率（OCR）来确定，而糖酵解使用细胞外酸化速率（ECAR）来测量，使用Seahorse XF分析仪。使用Pearson相关系数r检验OCR、ECAR和BRS之间的关联。 结果如下：RAS样肿瘤与OXPHOS相关基因的较高mRNA表达相关，如其mRNA表达与BRS - r之间的低至中度正相关性所证明的，范围从SDHB的0.28，p<0.001到细胞色素bc 1复合物的0.54，p<0.001。BRAF样肿瘤的特征在于糖酵解酶的更高表达，如其mRNA表达与BRS-r之间的低至强负相关性所证明的，BRS-r范围从己糖激酶II的-0.2至丙酮酸激酶的-0.65。同样，RAS样细胞系利用OXPHOS和糖酵解产生能量，而BRAF样细胞系的特征在于糖酵解表型和低OXPHOS率。BRS与OCR之间存在强正相关性（r=0.79，p=0.03），而BRS与ECAR之间无相关性（r=-0.12，p=0.82）。 结论：BRAF样和RAS样肿瘤的特征在于不同的代谢表型，RAS样肿瘤比BRAF样细胞更依赖OXPHOS。针对癌基因驱动的信号通路和不同的癌症代谢的治疗策略是必要的TC治疗的个性化方法。

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.