Within this action we studied how we balance the genomic information contained in our cells. Usually, all cells in our body, with the exception of egg cells (oocytes) and sperm, harbour two copies of the entire genetic information. In some organs, for example in the heart or in our liver, specialised cell types, such as cardiomyocytes or hepatocytes, respectively, contain a balanced increase in genomic information, a state that is referred to as polyploidy. We believe that polyploid cells can be more efficient and thereby strengthen organ function and output, but we also know that polyploid cells that grow and divide can make errors that potentially cause disease. However, polyploid cells are usually are very reluctant to re-enter the cell cycle or divide, which often limits organ regeneration after tissue damage. How the ability of polyploid cells to exit or reenter the cell cycle is regulated was poorly understood and our work helped to understand how polyploidy is controlled during organ development and how it impacts human pathologies, such as cancer and liver failure. We report that a molecular signaling platform, dubbed the PIDDosome, that controls cellular ploidy levels by limiting the proliferation of cells that accumulate extra centrosomes, that can be seen as a surrogate marker of a cell´s DNA content, is critical for ploidy control across tissues and organs. Centrosomes, structures that usually segregate genomic information during cell division have been linked to cancer for many years, but our work now also shows that these can have initial anti-tumorigenic effects by arresting or killing cancer cells. The objective of this study was to clarify the role of the PIDDosome as a barrier against malignant disease using diverse cellular and preclinical model systems, which could be confirmed in some but not all settings of cancer formation. In addition, we had reason to believe that centrosomes can also act as a hub for the induction of inflammation in response to errors in cell division, which adds a novel layer of regulation of innate and eventually also adaptive immune responses during pathogen-free sterile inflammation. Finally, we have established the relevance of this protein complex in controlling tissue development and regeneration in the liver and its impact on development of the heart. Here, we further provided proof of principle that manipulating ploidy levels in the liver can help to improve their ability to regeneration after tissue injury.
