Notch and p53 - how do they contribute to lung cancer tumorigenesis?

癌症是全球主要的死亡原因，预计其数量将进一步上升，2030年估计将导致1200万人死亡。在这些与癌症相关的死亡中，有很大一部分可归因于肺癌。虽然先进的技术，如下一代测序，可以更深入地了解癌细胞潜在的遗传损伤，但我们才刚刚开始了解由此产生的异常信号网络。保持基因组的完整性对地球上的任何生命都是必不可少的，以防止恶性转化。因此，强大的DNA监测系统--DNA损伤反应--已经演变出来。肿瘤抑制基因P53位于这个复杂的信号网络的核心，经常被发现在肺癌中具有功能突变。然而，目前仍不清楚为什么精通P53的肺癌在接受DNA破坏的化疗药物治疗后抵抗P53诱导的细胞凋亡。为了进一步阐明肺癌中P53介导的细胞凋亡的分子开关，我们将我们最近开发的P53报告鼠(Herter-Spre等人，未发表)与非小细胞肺癌和小细胞肺癌的小鼠模型进行杂交。其次，我们建议确定Notch信号异常如何影响肺癌的发生。越来越多的证据表明，Notch信号在不同的组织亚型肺癌中具有不同的功能，而且已有研究表明，P53熟练的肿瘤患者和Notch信号异常的患者显著降低了生存率。在这项研究中，我们旨在进一步研究Notch1作为肿瘤抑制因子的作用。为了实现这一目标，我们计划产生一种新的可重新激活的Notch等位基因，它可以在时间和空间上进行控制。最后，我们有兴趣对肺癌中Notch和P53之间的串扰有更深入的了解。

Cancer is the leading cause of death worldwide and its numbers are projected to rise further, resulting in an estimated 12 million deaths in 2030. A significant amount of these cancer-related deaths is attributable to lung cancer. Although advanced technologies such as next-generation sequencing permit a deeper insight into the underlying genetic lesions in cancerous cells, we only start to understand the resulting aberrant signaling networks. Maintaining genomic integrity is essential for any life on earth to prevent malignant transformation. Thus, powerful DNA surveillance systems - the DNA damage response - have evolved. The tumor suppressor p53 lies at the heart of this complex signaling network and is frequently found to have loss of function mutations in lung cancer. However, it still remains unclear why p53-proficient lung cancers resist p53-driven apoptosis after treatment with DNA-damaging chemotherapeutic agents. To further elucidate the molecular switches of p53-mediated apoptosis in lung cancer, we will cross our recently developed p53 reporter mouse (Herter-Sprie et al., unpublished) to mouse models of Non-Small Cell and Small Cell Lung Cancer. Secondly, we are proposing to determine how aberrant Notch signaling impacts on lung cancer tumorigenesis. Not only is there a growing body of evidence that Notch signaling has dichotomous functions on different histological subtypes of lung cancer, but also it had been shown that patients with p53-proficient tumors and aberrant Notch signaling have significantly reduced survival rates. In this study, we aim to further investigate the role of Notch1 as a tumor suppressor. To pursue this goal, we plan to generate a novel reactivatable Notch allele that can be controlled temporally and spatially. Finally, we are interested to gain a deeper insight into the crosstalk between Notch and p53 in lung cancer.