LBPO.MCB02 · 分子与细胞生物学 · Late-Breaking
Vhl-/-Tsc1-/-小鼠迅速发展出伴有显著代谢和氧化还原重编程的透明细胞肾细胞癌，且该重编程需要NRF2信号
Vhl-/-Tsc1-/- mice rapidly develop clear cell renal cell carcinoma with pronounced metabolic and redox reprogramming that necessitates NRF2 signaling
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作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌症基因组学提示，VHL和TSC1的联合遗传缺失足以在人类中引发透明细胞肾细胞癌（ccRCC）。在此，我们构建了一个肾脏特异性敲除Vhl和Tsc1的小鼠模型。Vhl-/-Tsc1-/-小鼠自7周龄起以100%外显率发展出多灶性肾细胞癌。这些Vhl-/-Tsc1-/-小鼠肾脏肿瘤模拟了人类VHL-/-TSC1-/-肾脏肿瘤的组织病理学特征。对4周龄癌前小鼠肾皮质的整合转录组学和代谢组学分析表明，Vhl-/-Tsc1-/-肾脏细胞不仅表现出增强的HIF和mTORC1信号，还启动了由核因子红细胞2相关因子2（NFE2L2或NRF2）调控的抗氧化反应。生化、细胞生物学、癌症多组学和异种移植研究发现了人类VHL-/-TSC1-/- ccRCC细胞的NRF2依赖性。总之，我们报道了一个重现人类VHL-/-TSC1-/- ccRCC的小鼠模型，阐明了肾皮质中HIF和mTORC1不受抑制激活时的代谢/氧化还原重编程，并提出了独特的治疗机会。
查看英文原文 English abstract
Cancer genomics implicated that combined genetic losses of VHL and TSC1 are sufficient to initiate clear cell renal cell carcinoma (ccRCC) in human. Here, we engineered a mouse model with kidney-specific deletion of Vhl and Tsc1 . Vhl -/- Tsc1 -/- mice developed multifocal renal cell carcinoma starting at 7 weeks of age with 100% penetrance. These Vhl -/- Tsc1 -/- mouse kidney tumors mimicked the histopathology of human VHL -/- TSC1 -/- kidney tumors. Integrated transcriptomic and metabolomic analyses of 4-week-old precancerous mouse kidney cortex demonstrated that Vhl -/- Tsc1 -/- kidney cells not only exhibit heightened HIF and mTORC1 signals but also engage antioxidant response regulated by the Nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). Biochemical, cell biological, cancer multi-omic, and xenograft studies discovered NRF2-dependence in human VHL -/- TSC1 -/- ccRCC cells. Altogether, we report a mouse model recapitulating human VHL -/- TSC1 -/- ccRCC, delineate metabolic/redox reprogramming upon unbridled HIF and mTORC1 activation in the kidney cortex, and present unique therapeutic opportunities.
利益披露 Disclosure
X. Cheng, None..
J. Xu, None..
O. A. Aboud, None..
Y. Chen, None..
E. Reznik, None..
T. Oyama, None..
S. Tickoo, None..
E. H. Cheng, None..
R. H. Weiss, None..
J. J. Hsieh, None.