p53 mutations show diverse impact on pancreatic cancer metabolism

A research team at the University of Konstanz, led by toxicologist Ivano Amelio, has demonstrated how differently individual mutations of the tumor suppressor p53 affect pancreatic carcinomas.

When cell growth gets out of control and malignant cells begin to proliferate, cancer can develop in a process known as tumorigenesis. There are always errors in cell division in every body, but sophisticated mechanisms normally ensure that only healthy cells duplicate and damaged cells die – in other words, that tumors do not emerge in the first place. One helper in this process is the p53 protein. However, when it mutates, it can no longer fulfil its task. Until now, researchers have assumed that the process is the same with all mutation types. Within the framework of a DFG-funded Collaborative Research Centre (Transregio 353 “Regulation of cell death decisions”), a research team from the University of Konstanz has now shown that different mutations have different effects on cell metabolism.

How p53 works

In case of DNA damage, the p53 protein has the task of blocking the proliferation of the affected cell, thus providing extra time for repairs. Should this repair fail, the cell self-destructs and makes room for a new one that is as flawless as possible. This process is important to ensure that only healthy cells multiply and that uncontrolled proliferation (e.g. cancer) does not occur.

However, p53 can mutate and is then no longer able to entirely fulfil its actual function: Cell growth is no longer delayed, there is no time for repairs and cell death is not initiated. As a result, the degenerated cell eventually multiplies and a tumor can grow. In about every second case of tumor such a mutation of the p53 protein can be detected. Cancer researchers are therefore striving to better understand and counteract the mutations.

Not all mutations are the same

A research team at the University of Konstanz, led by toxicologist Ivano Amelio, has made good progress in this direction. In a recent study, they compared two mutations of the p53 protein and were able to show that they have different effects on the metabolism of pancreatic carcinomas. “Our study showed that the first variant maintains the mitochondrial function and energy production of the cell and at the same time influences the cellular antioxidant capacity. The second variant did not show this influence, but instead dampened the activation of pro-tumor metabolic pathways, such as the urea cycle”, says Amelio, summarising the results of the study. The finding that the two mutations of the p53 protein selectively control different metabolic pathways in pancreatic carcinomas opens up new avenues in cancer research.

Previous research has largely assumed that differentiating between the mutation variants of p53 is not all that important, but only the fact that there is a mutation counts”, says the toxicologist, adding: “This assumption has fostered debate around contradicting observations in the field. Our results emphasise the need to no longer view the mutation variants as a homogeneous group, but to systematically examine each variant individually”. According to Amelio, we are only just beginning to understand the real relevance of p53 mutant proteins. Only systematic analyses using models that reflect the tumor ecology more precisely will give us a deeper insight.

Key facts:

• Paper on the study: Caporali, S., Butera, A., Ruzza, A. et al. Selective metabolic regulations by p53 mutant variants in pancreatic cancer. J Exp Clin Cancer Res 43, 310 (2024). Journal Impact Factor: 11,4.:
• Perspective paper on the topic: Butera A, Amelio I. Deciphering the significance of p53 mutant proteins. Trends Cell Biol. 2024 Jul 2:S0962-8924(24)00117-X. Journal Impact Factor: 13,0: doi: 10.1016/j.tcb.2024.06.003
• Professor Ivano Amelio is a professor of toxicology at the University of Konstanz. The focus of his work is on research into the molecular basis of cancer. He is president of the European Cell Death Organization (ECDO) and editor-in-chief of the CDDpress journal “Cell Death Discovery”.
• The DFG-funded Collaborative Research Centre TRR 353 “Regulation of cell death decisions” investigates the fundamental principles of cell death decisions in basic biology and human pathology.