Department of Oncology, University of Cambridge, CRUK Cambridge institute, Cambridge, CB2 0RE, UK.
MedImmune, AstraZeneca, Cambridge, CB21 6GH, UK.
Nat Commun. 2017 Dec 11;8(1):2026. doi: 10.1038/s41467-017-02245-1.
Inactivation of the VHL (Von Hippel Lindau) tumour suppressor has long been recognised as necessary for the pathogenesis of clear cell renal cancer (ccRCC); however, the molecular mechanisms underlying transformation and the requirement for additional genetic hits remain unclear. Here, we show that loss of VHL alone results in DNA replication stress and damage accumulation, effects that constrain cellular growth and transformation. By contrast, concomitant loss of the chromatin remodelling factor PBRM1 (mutated in 40% of ccRCC) rescues VHL-induced replication stress, maintaining cellular fitness and allowing proliferation. In line with these data we demonstrate that combined deletion of Vhl and Pbrm1 in the mouse kidney is sufficient for the development of fully-penetrant, multifocal carcinomas, closely mimicking human ccRCC. Our results illustrate how VHL and PBRM1 co-operate to drive renal transformation and uncover replication stress as an underlying vulnerability of all VHL mutated renal cancers that could be therapeutically exploited.
长期以来，VHL（von Hippel-Lindau）肿瘤抑制因子的失活被认为是透明细胞肾细胞癌（ccRCC）发病机制的必要条件；然而，转化的分子机制以及对额外遗传打击的需求仍不清楚。在这里，我们表明，单独失去 VHL 会导致 DNA 复制应激和损伤积累，这些影响限制了细胞生长和转化。相比之下，伴随的染色质重塑因子 PBRM1（40%的 ccRCC 中发生突变）的缺失可以挽救 VHL 诱导的复制应激，维持细胞适应性并允许增殖。与这些数据一致，我们证明了在小鼠肾脏中同时缺失 Vhl 和 Pbrm1 足以发展出完全穿透性、多灶性的癌，这与人类 ccRCC 非常相似。我们的研究结果说明了 VHL 和 PBRM1 如何合作驱动肾转化，并揭示了复制应激是所有 VHL 突变的肾肿瘤的潜在脆弱性，这可能为治疗提供靶点。
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