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

Notch 和 p53 - 它们如何促进肺癌肿瘤发生？

• 批准号: 235233054
• 负责人: Dr. Grit Sophie Herter-Sprie
• 金额: --
• 依托单位: Klinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/235233054?language=en
• 关键词: Notch; p53; how; do; they

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of p53-mediated apoptosis in lung cancer, we will cross our recently developed p53 reporter mouse (Herter-Sprie et al., unpublished) to mouse models of Non-Small Cell and Small Cell Lung Cancer.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.

癌症是全世界死亡的主要原因，其数量预计将进一步上升，估计到2030年将导致1200万人死亡。这些与癌症有关的死亡中有相当一部分可归因于肺癌。尽管下一代测序等先进技术可以更深入地了解癌细胞中潜在的遗传病变，但我们才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于地球上的任何生命都是至关重要的，以防止恶性转化。因此，强大的DNA监视系统-DNA损伤反应-已经进化。肿瘤抑制因子p53位于这个复杂信号网络的核心，并且经常被发现在肺癌中具有功能缺失突变。然而，目前仍不清楚为什么p53-熟练的肺癌抵抗p53驱动的细胞凋亡后，与DNA损伤化疗药物治疗。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报告小鼠（Herter-Sprie等人，未发表）用于非小细胞和小细胞肺癌的小鼠模型。其次，我们正在研究Notch信号异常对肺癌发生的影响。不仅有越来越多的证据表明Notch信号在不同组织学亚型的肺癌中具有二分功能，而且已经表明，具有p53活性肿瘤和异常Notch信号的患者的生存率显著降低。在这项研究中，我们的目的是进一步研究Notch 1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再激活的Notch等位基因，该等位基因可以在时间和空间上进行控制。最后，我们有兴趣更深入地了解肺癌中Notch和p53之间的串扰。