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

• Applicant: Dr. Grit Sophie Herter-Sprie
• Subject Area: Hematology, Oncology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 235233054

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p53-mediated apoptosis in lung cancer, we will cross our recently developed p53 reporter mouse (Herter-Sprie et al., unpublished) to mouse models of Non-Small Cell and Small Cell Lung Cancer.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

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Kwok-Kin Wong