Renal cell carcinoma (RCC) has emerged as a metabolic disease characterized by dysregulated expression of metabolic enzymes. Patients with metastatic RCC have an unusually poor prognosis and near-universal resistance to all current therapies. To improve RCC treatment and the survival rate of patients with RCC, there is an urgent need to reveal the mechanisms by which metabolic reprogramming regulates aberrant signaling and oncogenic progression. Through an integrated analysis of RCC metabolic pathways, we showed that methylthioadenosine phosphorylase (MTAP) and its substrate methylthioadenosine (MTA) are dysregulated in aggressive RCC. A decrease in MTAP expression was observed in RCC tissues and correlated with higher tumor grade and shorter overall survival. Genetic manipulation of MTAP demonstrated that MTAP expression inhibits the epithelial-mesenchymal transition, invasion and migration of RCC cells. Interestingly, we found a decrease in the protein methylation level with a concomitant increase in tyrosine phosphorylation after MTAP knockout. A phospho-kinase array screen identified the type 1 insulin-like growth factor-1 receptor (IGF1R) as the candidate with the highest upregulation in tyrosine phosphorylation in response to MTAP loss. We further demonstrated that IGF1R phosphorylation acts upstream of Src and STAT3 signaling in MTAP-knockout RCC cells. IGF1R suppression by a selective inhibitor of IGF1R, linsitinib, impaired the cell migration and invasion capability of MTAP-deleted cells. Surprisingly, an increase in linsitinib-mediated cytotoxicity occurred in RCC cells with MTAP deficiency. Our data suggest that IGF1R signaling is a driver pathway that contributes to the aggressive nature of MTAP-deleted RCC.

肾细胞癌（RCC）已经出现，是一种以代谢酶表达失调为特征的代谢疾病。转移性RCC患者的预后异常差，并且对所有当前疗法的抵抗力几乎普遍。为了改善RCC治疗和RCC患者的存活率，迫切需要揭示代谢重编程调节异常信号传导和致癌进展的机制。通过对RCC代谢途径的综合分析，我们发现在侵袭性RCC中甲基硫代腺苷磷酸化酶（MTAP）及其底物甲基硫代腺苷（MTA）失调。在RCC组织中观察到MTAP表达下降，并且与更高的肿瘤等级和更短的总生存期相关。MTAP的遗传操作表明MTAP表达抑制RCC细胞的上皮-间质转化，侵袭和迁移。有趣的是，我们发现敲除MTAP后蛋白质甲基化水平降低，酪氨酸磷酸化水平随之升高。磷酸激酶阵列筛选将1型胰岛素样生长因子-1受体（IGF1R）识别为响应MTAP丢失而酪氨酸磷酸化上调最高的候选药物。我们进一步证明，IGF1R磷酸化作用在MTAP敲除RCC细胞中Src和STAT3信号传导的上游。IGF1R的选择性抑制剂linsitinib对IGF1R的抑制作用削弱了MTAP缺失细胞的细胞迁移和侵袭能力。出乎意料的是，在MTAP缺乏的RCC细胞中，林西替尼介导的细胞毒性增加。