Novel effectors of Kras in oncogenesis, senescence and tumor progression

描述（由申请人提供）：KRAS是最常突变的人类癌基因之一。在某些情况下，致癌KRAS可以触发细胞衰老，而在其他情况下，表达导致过度增殖。鉴于KRAS突变在人类癌症中的重要性，阐明调节这两种截然不同结果的机制将有助于确定RAS驱动的癌症的新治疗方法。我们已经确定了一个新的作用，肾母细胞瘤-1（WT 1）作为一个关键的调节衰老和增殖的致癌KRAS下游。Wt 1的缺失导致小鼠原代细胞和人肿瘤细胞以致癌KRAS依赖性方式衰老。此外，在肺癌小鼠模型中，WT 1表达在化学抗性肿瘤细胞中特异性上调。这些发现揭示了WT 1作为KRAS下游遗传网络的关键调节因子的意想不到的作用，并表明Wt 1在化学抗性中的关键作用。在这个建议中，我们将使用分子，遗传和生物化学方法的组合来阐明致癌KRAS和WT 1之间观察到的相互作用的机制基础。初步数据表明，WT 1的作用至少有一部分是由RNA的转录后调节介导的。因此，本提案将使用最先进的方法来分析Wt 1在剪接和蛋白质翻译中的作用。此外，我们将确定WT 1在调节KRAS驱动的肺肿瘤化疗耐药性中的作用。 公共卫生相关性：KRAS是人类癌症中最常见的突变癌基因之一。然而，KRAS突变在某些情况下（组织）导致癌症而在其他情况下不会导致癌症的原因尚未完全了解。我们已经确定了KRAS引起细胞增殖的能力与Wilm's tumor-1（WT 1）表达之间的新联系。该提案将侧重于了解这种相互作用对肿瘤发生，衰老和化疗反应的机制和后果。

DESCRIPTION (provided by applicant): KRAS is one of the most frequently mutated human oncogenes. In some settings oncogenic KRAS can trigger cellular senescence, whereas in others expression leads to hyperproliferation. Given the importance of KRAS mutation in human cancer, elucidating the mechanisms regulating these two drastically distinct outcomes would help identify novel therapeutic approaches in RAS-driven cancers. We have identified a novel role for Wilms tumor-1 (WT1) as a critical regulator of senescence and proliferation downstream of oncogenic KRAS. Loss of Wt1 leads to senescence in mouse primary cells and human tumor cells in an oncogenic KRAS- dependent manner. In addition, WT1 expression is specifically upregulated in chemoresistant tumor cells in a mouse model of lung cancer. These findings reveal an unexpected role for WT1 as a key regulator of the genetic network downstream of KRAS and suggest a key role for Wt1 in chemoresistance. In this proposal, we will use a combination of molecular, genetic and biochemical approaches to elucidate the mechanistic basis for the observed interaction between oncogenic KRAS and WT1. Preliminary data suggests that at least part of the role of WT1 is mediated by post-transcriptional regulation of RNAs. Thus, this proposal will use state-of- the-art approaches to analyze the role of Wt1 on splicing and protein translation. In addition, we will determine the role of WT1 in regulating chemotherapy resistance in KRAS-driven lung tumors. PUBLIC HEALTH RELEVANCE: KRAS is one of the most frequently mutated oncogenes in human cancer. However, the reason why KRAS mutation leads to cancer in some contexts (tissues) but not in others is not completely understood. We have identified a novel connection between the ability of KRAS to cause cells to proliferate and the expression of Wilm's tumor-1 (WT1). This proposal will focus on understanding the mechanisms and consequences of this interaction for tumor initiation, senescence and chemotherapy response.