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Molecular mechanisms of induced protection against sepsis by DNA damage responses

Periodic Reporting for period 3 - iPROTECTION (Molecular mechanisms of induced protection against sepsis by DNA damage responses)

Reporting period: 2018-10-01 to 2020-03-31

Our laboratory investigates the mechanisms used to restore homeostasis when an organism responds to different types of stress. We focus on the events triggered by DNA damage, such as those caused by drugs used in chemotherapy to treat cancer, because we have recently found that when used at low doses they can have a surprising but strong protective effect against systemic infections (sepsis) and other conditions that cause substantial tissue damage and organ dysfunction. In addition to its biological interest and significance, our work is also important because there are practical implications for our findings, including for the treatment of sepsis (that has no specific treatment so far and is responsible for over 6 million deaths worldwide every year).
The central goal of the current proposal is to identify and characterize novel cytoprotective mechanisms, with a focus on DNA damage response dependent protection activated by anthracyclines (the most commonly used chemotherapeutic drugs to treat cancer) as a window into stress-induced genetic programs conferring disease tolerance.
During the first 30 months of this project we have investigated the molecular mechanisms of DNA damage induced protection against sepsis, by exploring the transcription profiles induced by anthracyclines, their dependence on ATM and ATR. We have also explored the effects of these drugs in the metabolic profiles of immune competent and parenchymal cells. We have started to take unbiased approaches to uncover novels cytoprotective mechanisms induced by DNA damage using model organisms. In addition, we have been developing the tools to study the centrality of the lung in sepsis.

So far, we found important new cues into the molecular mechanisms of disease tolerance induction by DNA damage responses. Our main and most advanced results relate to the precise identification of the molecular mechanism by which anthracyclines specifically block the transcription of NFkB targets, when used at concentration below cytotoxic levels. In the course of this investigation, we also found that low levels of DNA damage promote survival against TNF-induced cell death, in an NFkB-independent manner. We are currently preparing a manuscript to report on our findings, while performing key experiments to more conclusively show the impact and relevance of our findings.
Our observation that low level DNA damage caused by anthracyclines is able to prevent TNF-induced cell death in an NFkB-independent manner is completely unexpected and substantially goes beyond the state of the art. This is especially surprising because in the same conditions these drugs inhibit NFkB, contrary to the dogma in the field that accepts that these drugs activate NFkB, because they are normally used at very high doses as the goal is to kill cancer cells. Our discovery has critical importance in the field of cancer treatment as it uncovers a possible key mechanism to explain the emergence of resistance against chemotherapy, while pointing into novel strategies to develop more effective therapies against cancer. In fact, even when used at high doses to treat cancer, if the tumor is large, or it is located in a tissue or organ where doses do not reach the necessary levels, a substantial number of cells will be exposed to sub-optimal doses, in which case these drugs will promote cell survival and not cell death as intended. This is especially dangerous as it probably happens in the setting of DNA damage which adds cell survival to induced mutations, leading not only to cancer resistance to chemotherapy but also to the emergence of more aggressive forms of the tumor. If confirmed, the impact is therefore very high as chemotherapy resistance is a major problem in the treatment of cancer. Our discovery opens the possibility of rational design of new and more effective combinatorial therapies in cancer. In addition, from the opposite perspective, can also be explored to increase tissue regeneration and survival in conditions that cause substantial tissue damage including ischemia / reperfusion diseases.