Periodic Reporting for period 4 - POLICE (The PIDDosome in Centrosome and Ploidy-Surveillance)
Periodo di rendicontazione: 2023-04-01 al 2024-09-30
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.
The main results achieved in the last period can be summarized as follows.
1) In normal blood cells and oncogene-driven blood cancer, increased centrosome numbers are seen as a danger signal that elicits the rapid death of such cells by the induction of apoptosis.
2) Extra centrosomes can act as “danger signals” in the cell and prevent the onset of malignant disease induced by DNA damage, e.g. in the blood, or in soft tissue sarcoma, likely by lowering cell death thresholds in premalignant cells.
3) In preliminary exploratory work, we also realised that loss of PIDDosome function promotes hyperactivation of osteoclast function and osteoporosis, establishing the PIDDosome as a ploidy regulator across tissues and independent of the mode how polyploidy is achieved in cells.
1) In normal blood cells and oncogene-driven blood cancer, increased centrosome numbers are seen as a danger signal that elicits the rapid death of such cells by the induction of apoptosis.
2) Extra centrosomes can act as “danger signals” in the cell and prevent the onset of malignant disease induced by DNA damage, e.g. in the blood, or in soft tissue sarcoma, likely by lowering cell death thresholds in premalignant cells.
3) In preliminary exploratory work, we also realised that loss of PIDDosome function promotes hyperactivation of osteoclast function and osteoporosis, establishing the PIDDosome as a ploidy regulator across tissues and independent of the mode how polyploidy is achieved in cells.
Our studies have charted unknown territory by defining a new cellular mechanisms that controls the upper limit of the DNA content in specialized cell types, such as cardiomyocytes and hepatocytes, as well as osteoclasts. This establishes that the PIDDosome complex acts as a general ploidy sensor by "counting" the number of extra centrosomes. We postulate that this is likely also true in other cell types, such as binucleated epithelial cells in the mammary gland and ureter, or platelet producing megakaryocytes. Targeting this signalling complex, either genetically or pharmacologically, can hence be beneficial in certain pathological situations linked to the impaired proliferation of these cell types, or reduced regeneration capacity of their relevant host organs and tissues. We anticipate that we can develop the PIDDosome into an attractive drug target in regenerative medicine and have started to collaborate with a company developing inhibitors specific for Caspase-2.