Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade.
Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade.
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小鼠肾细胞癌建模：Bap1 和 Pbrm1 失活驱动肿瘤分级。
DOI：
10.1158/2159-8290.cd-17-0292
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发表时间：
2017-08
期刊：
影响因子：
28.2
通讯作者：
Brugarolas J
中科院分区：
文献类型：
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作者：
Gu YF;Cohn S;Christie A;McKenzie T;Wolff N;Do QN;Madhuranthakam AJ;Pedrosa I;Wang T;Dey A;Busslinger M;Xie XJ;Hammer RE;McKay RM;Kapur P;Brugarolas J
肾透明细胞癌(CcRCC)以BAP1和PBRM1突变为特征，与不同级别和预后的肿瘤相关。然而，BAP1和PBRM1缺失是否会导致ccRCC并决定肿瘤分级尚不清楚。我们使用几个CRE驱动程序在小鼠中有条件地靶向BAP1和PBRM1(带有VHL)。SGLT2和Villin近端曲管驱动因素未能导致肿瘤发生，挑战了ccRCC起源的传统观念。相反，以发育谱系特异性转录因子Pax8为靶点，会导致不同级别的ccRCC。与潜伏期较长的PBRM1基因缺陷的肿瘤相比，BAP1基因缺陷的肿瘤分级较高，mTORC1激活程度更高。在PBRM1缺陷的肾脏中，干扰mTORC1负性调节基因TSC1的一个等位基因会引发更高级别的ccRCC。本研究建立了BAP1和PBRM1作为ccRCC和组织学分级的谱系特异性驱动因素，暗示mTORC1是肿瘤级别的变阻器，并提示ccRCC可能来自Bowman囊细胞。
Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 mutation, which are associated with tumors of different grade and prognosis. However, whether BAP1 and PBRM1 loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted Bap1 and Pbrm1 (with Vhl) in the mouse using several Cre drivers. Sglt2 and Villin proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with Pax8, a developmental lineage-specific transcription factor, led to ccRCC of different grade. Bap1-deficient tumors were high grade and showed greater mTORC1 activation than Pbrm1-deficient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, Tsc1, in Pbrm1-deficient kidneys triggered higher grade ccRCC. This study establishes Bap1 and Pbrm1 as lineage-specific drivers of ccRCC and histological grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCC may arise from Bowman capsule cells.