Final Report Summary - PICHO (p53 control of epithelial homeostasis)
p53 is a multi-purpose tumor suppressor, fulfilling its roles both at individual cells and at tissue levels, affecting the relationship of the different cells within a tissue. An example for a tissue level function of p53 is the prevention of invasion, for example preventing the invasion of transformed gut epithelial cells into the lamina propria. Since we discovered this anti-invasion role, many other tissue regulatory functions were found to be affected by p53, including metabolism and inflammation control. p53 is mutated or inactivated in the majority of human cancers and then, both the cell-autonomous and the tissue control functions of p53 are compromised, contributing to the progression of cancer. Our ERC project aimed to decipher some of the tissue functions of p53, particularly in the gut, but in the course of the project we observed tissue functional effects of p53 also in other tissues, such as the skin and the hematopoietic system.
A major lesson learned through the ERC project is the tight association between p53 and inflammatory processes. p53 is not mutated evenly in all cancer types and the reasons for this disparity are unknown. We identified a low grade inflammatory process, which unlike other types of inflammation, is confined to epithelial tissues and is not associated with inflammatory cell infiltrates and can therefore cannot be detected under microscope or through any of the four classical signs of inflammation, color, dolor, tumor and rubor, only by the fifth sign, malfunction and a unique inflammatory gene expression signature. We denoted this variant inflammatory process parainflammation, a term coined by Ruslan Medzhitov to describe basal inflammatory condition falling within normal homeostasis. Parainflammation is not observed in healthy tissues, yet occurs in 30% of all human solid tumors and is tightly linked to p53. Cancer types distinguished by parainflammation are in general highly mutated in p53, which led us to speculate that p53 mutations in cancer may be driven by parainflammation.
Parainflammation (PI) appears to affect tissue stem cells. An interesting example is intestinal stem cells, which following injury, as after irradiation and certain other types of stress die, yet before dying the cells release at least one PI factor, TNF. This factor activates dormant reserve stem cells in the gut, thus enabling the replacement of the dying stem cells and preserving the gut. This PI-controlled rescue process is again tightly linked to p53, which is needed to vacate the intestinal niches of the injured stem cells for the fresh replacing cells.
One of the more significant achievements of our ERC project is the success in developing small molecule inhibitors of CKIα, which turned out to be one of the most effective means of p53 activation. Using these inhibitors, we already proved the capacity to eliminate cancer stem selectively via p53 activation. We have employed these inhibitors for leukemia therapy in a mouse model of a very aggressive disease and showed that a significant portion of the treated mice are cured of the disease, a milestone that has hardly ever achieved in this model or related ones. On the basis of these studies, these small molecule inhibitors are being developed now for human cancer therapy.
A major lesson learned through the ERC project is the tight association between p53 and inflammatory processes. p53 is not mutated evenly in all cancer types and the reasons for this disparity are unknown. We identified a low grade inflammatory process, which unlike other types of inflammation, is confined to epithelial tissues and is not associated with inflammatory cell infiltrates and can therefore cannot be detected under microscope or through any of the four classical signs of inflammation, color, dolor, tumor and rubor, only by the fifth sign, malfunction and a unique inflammatory gene expression signature. We denoted this variant inflammatory process parainflammation, a term coined by Ruslan Medzhitov to describe basal inflammatory condition falling within normal homeostasis. Parainflammation is not observed in healthy tissues, yet occurs in 30% of all human solid tumors and is tightly linked to p53. Cancer types distinguished by parainflammation are in general highly mutated in p53, which led us to speculate that p53 mutations in cancer may be driven by parainflammation.
Parainflammation (PI) appears to affect tissue stem cells. An interesting example is intestinal stem cells, which following injury, as after irradiation and certain other types of stress die, yet before dying the cells release at least one PI factor, TNF. This factor activates dormant reserve stem cells in the gut, thus enabling the replacement of the dying stem cells and preserving the gut. This PI-controlled rescue process is again tightly linked to p53, which is needed to vacate the intestinal niches of the injured stem cells for the fresh replacing cells.
One of the more significant achievements of our ERC project is the success in developing small molecule inhibitors of CKIα, which turned out to be one of the most effective means of p53 activation. Using these inhibitors, we already proved the capacity to eliminate cancer stem selectively via p53 activation. We have employed these inhibitors for leukemia therapy in a mouse model of a very aggressive disease and showed that a significant portion of the treated mice are cured of the disease, a milestone that has hardly ever achieved in this model or related ones. On the basis of these studies, these small molecule inhibitors are being developed now for human cancer therapy.