Periodic Reporting for period 3 - POLICE (The PIDDosome in Centrosome and Ploidy-Surveillance)
Reporting period: 2021-10-01 to 2023-03-31
The issue addressed in this action is to understand 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, harbor two copies of the entire information stored in our genes. In some organs, for example in the heart or in our liver, specialized cell types 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 the organ, but we also know that polyploid cells that grow and divide make errors that can cause disease. However, polyploid cells are usually are very reluctant to re-enter the cell cycle and divide, which often limits organ regeneration after tissue damage. How the ability of polyploid cells to exit or reenter the cell cycle is regulated is not understood in full detail, but it is critical for us to understand certain human pathologies, such as cancer, cardiac hypertrophy or liver failure.
In earlier work, have identified a molecular signaling platform, dubbed the PIDDosome, that controls cellular ploidy levels by limiting the proliferation of cells that harbor extra centrosomes, that can be seen as a surrogate marker of a cell´s DNA content, i.e. ploidy level. These structures that usually segregate genomic information during cell division evenly between daughter cells also need to be duplicated during the cell cycle, alongside with DNA.
The objective of this study is to clarify the role of the PIDDosome as a barrier against malignant disease using diverse cellular and preclinical model systems. In addition, we have reason to believe that centrosomes can also act as a hub for the induction of inflammation in response to errors in cell division, which would add a novel layer of regulation of innate and eventually also adaptive immune responses in a processes referred to as sterile inflammation. Finally, we have started to investigate the relevance of this protein complex in controlling tissue development and regeneration, focusing on the liver and the heart. Here, we aim for a proof of principle that manipulating ploidy levels in these organs can help to improve their ability or time needed for regeneration after tissue injury.
In earlier work, have identified a molecular signaling platform, dubbed the PIDDosome, that controls cellular ploidy levels by limiting the proliferation of cells that harbor extra centrosomes, that can be seen as a surrogate marker of a cell´s DNA content, i.e. ploidy level. These structures that usually segregate genomic information during cell division evenly between daughter cells also need to be duplicated during the cell cycle, alongside with DNA.
The objective of this study is to clarify the role of the PIDDosome as a barrier against malignant disease using diverse cellular and preclinical model systems. In addition, we have reason to believe that centrosomes can also act as a hub for the induction of inflammation in response to errors in cell division, which would add a novel layer of regulation of innate and eventually also adaptive immune responses in a processes referred to as sterile inflammation. Finally, we have started to investigate the relevance of this protein complex in controlling tissue development and regeneration, focusing on the liver and the heart. Here, we aim for a proof of principle that manipulating ploidy levels in these organs can help to improve their ability or time needed for regeneration after tissue injury.
The main results achieved so far can be summarized as follows.
1) In liver cancer, increased DNA content can actually be protective an delay development of malignant disease, a novel and unexpected finding. Moreover, analysis of human liver cancer tissue suggests that nuclear size, as a surrogate for the cellular DNA content, can be used as a prognostic marker and predict the prognosis of patients suffering from hepatocellular carcinoma.
2) Extra centrosomes can act as “danger signals” in the cell by eliciting an inflammatory response upon failed cell division. This suggests that cells of the innate immune system may become aware of such cells that are in danger to distribute their DNA content unevenly and prime them for immune attack.
3) We have demonstrated that the development and regeneration of the liver is regulated in part by the PIDDosome complex and that its inhibition may be a suitable means to speed up liver regeneration, as humans seem to exploit the same signalling network to control liver ploidy during regenerative liver growth. Finally, early results suggest that a similar mechanism is at play in the developing heart.
1) In liver cancer, increased DNA content can actually be protective an delay development of malignant disease, a novel and unexpected finding. Moreover, analysis of human liver cancer tissue suggests that nuclear size, as a surrogate for the cellular DNA content, can be used as a prognostic marker and predict the prognosis of patients suffering from hepatocellular carcinoma.
2) Extra centrosomes can act as “danger signals” in the cell by eliciting an inflammatory response upon failed cell division. This suggests that cells of the innate immune system may become aware of such cells that are in danger to distribute their DNA content unevenly and prime them for immune attack.
3) We have demonstrated that the development and regeneration of the liver is regulated in part by the PIDDosome complex and that its inhibition may be a suitable means to speed up liver regeneration, as humans seem to exploit the same signalling network to control liver ploidy during regenerative liver growth. Finally, early results suggest that a similar mechanism is at play in the developing heart.
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. This suggests that the PIDDosome complex might act as a general ploidy sensor by counting the number of extra centrosomes also in other cell types, such as bone resorbing osteoclasts, 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 until the end of our action.