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p73 dependence in cancer: from molecular mechanisms to therapeutic targeting

Final Report Summary - P73CANCER (p73 dependence in cancer: from molecular mechanisms to therapeutic targeting)

Cancer is a genetic disease caused by acquired or inherited gene mutations. The most frequently mutated gene across all cancer types is the tumor suppressor gene p53, which is one member of the p53 gene family comprising the p53, p63 and p73. Our research was focused on understanding how disruption of the cancer protective role of the p53 gene family leads to cancer development and identifying mechanisms to restore the tumor suppressive function for improved cancer therapy.

p53 mutations cluster in the DNA binding region which underlines that p53 needs to bind DNA for protecting us from cancer. We have shown that p53 molecules cooperate for DNA binding and that it is possible to fine-tune DNA binding by modulating the degree of cooperation (Schlereth et al., Mol Cell 2010; Schlereth et al., Plos Genet 2013). Using a new genetically-engineered mouse model we have demonstrated that mutations which compromise this cooperation of p53 molecules interfere with the elimination of incipient cancer cells from the organism by programmed cell death and result in tumor susceptibility (Timofeev et al., Cell Reports 2013). These studies have pinpointed disruption of the p53 quarternary structure as a novel mechanism by which p53 gene mutations drive cancer development. Other p53 mutations were identified to increase folding and maturation of cell surface proteins thereby rendering tumor cells more invasive and metastatic (Vogiatzi et al., PNAS in press). In addition, by critically evaluating the target-specificity of p53-reactivating compounds using gene editing we have unmasked the presumptive p53-reactivating compound RITA as p53 non-specific (Wanzel et al., Nat Chem Biol 2016).

In stark contrast to p53, the family member p73 is not commonly mutated in cancer patients. In fact, p73 is often found at elevated levels in cancer cells, which suggests that p73 promotes rather than inhibits cancer development. On the other hand, mice with an engineered deletion of the p73 gene suffer from cancer susceptibility in support of a p53-like cancer-protective effect of p73. To reconcile these on first sight contradictory data, we hypothesize that p73 has both cancer-protective and tumorpromoting activities and that cancer cells during their development selectively turn off the cancerprotective functions and learn to profit from the remaining tumor-promoting activities (reviewed in Maas et al., Cancer Lett 2013). The P73CANCER project has revealed tumor subtypes that are characterized by high levels of p73 and demonstrated that genetic and epigenetic gene alterations result in elevated expression of p73-inhibitory isoforms that become essential for tumor growth and confer vulnerabilities that could be exploited for cancer therapy. In addition, we demonstrated that amplification of the p63 gene in squamous cell carcinomas of the lung and head and neck region does not inhibit p73 as previously claimed and instead enhances cellular DNA repair thereby limiting the efficacy of classical chemotherapy (Bretz et al., Nucleic Acids Research 2016).

In the course of the project we encountered a need to improve methods to quantitatively measure growth and therapy responses of tumors in preclinical mouse models. We developed a method using light-emitting proteins, so-called luciferases, as an artificial tumor marker that is secreted by tumor cells into the blood (Charles et al., Nat Commun 2014). The amount of luciferase in the blood can be measured in single drop of blood and accurately reflects the total amount of tumor cells in the body. We demonstrate that this method improves the quantitative analysis of tumor growth in mouse experiments and simultaneous reduces animal numbers and burden according to the 3R principle “Replace, Reduce, Refine”.

In summary, the project has provided new insight into the role of p53 and p73 in preventing cancer development, identified perspectives for therapeutic targeting of cancer cells through p53 family members and developed methods that help to improve animal welfare in cancer research.