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NLRP3 in cancer: Deciphering the role of NLRP3 in the DNA Damage response pathway

Periodic Reporting for period 1 - RoNDBioCan (NLRP3 in cancer: Deciphering the role of NLRP3 in the DNA Damage response pathway)

Reporting period: 2018-01-01 to 2019-12-31

The identification of new therapeutic strategies in the treatment of lung cancer is a research priority. Today 40% of these cancers remain of undetermined origin, so there is a crucial need to identify new mechanisms behind lung cancer. The action of current therapies relies mainly on the induction of highly toxic DNA lesions, where side-effects themselves lead to considerable morbidity and mortality. The MSCA project RoNDBioCan “Deciphering the Role of NLRP3 in the DNA Damage Response (DDR) pathway and evaluation of the potential predictive role of NLRP3 as a Biomarker in the treatment of lung Cancer” aims at understanding the molecular processes driving lung cancer.
Tumors cells causes inflammation within a tissue. If the main role of inflammation is to participate in the elimination of tumors, multiple studies show that it also promotes their development. In our lab, we study an immune factor called NLRP3 involved in a protein complex called NLRP3 inflammasome. The aim of this complex is to secrete inflammatory cytokines involved in the immune response. Evidence has shown that NLRP3 is deregulated in a wide range of disorders, and its expression is systematically absent in lung cancer cells. Interestingly, our research group showed that NLRP3 is also an important factor for the response to DNA damage. Poor repair of these alterations could have insidious effects by causing the appearance of mutations, thus promoting the process of carcinogenesis. It is therefore crucial to better understand how the different functions of NLRP3 are regulated.
The objectives of this Marie Sklodowska Curie Action (MSCA) were to (1) decipher the molecular mechanism of NLRP3 function in the DDR pathway in non-tumoral and tumoral lung epithelial cells and to (2) evaluate the predictive role of NLRP3 expression in response to chemotherapy in the treatment of lung cancer. Another objective of the MSCA individual fellowship was to promote the development of the individual researcher and to sensitize a broad public to MSCA.
At the scientific level, RoNDBioCan contributed significantly to european excellence and society in that it has strengthen the knowledge of lung tumorigenesis and helped the career development of the fellow.
"The RoNDBioCan project was organized in down in 6 work-packages: WP1 deeply characterized NLRP3 function in response to chemotherapeutic treatments. WP2 and WP3 studied the effect of NLRP3 expression on cell sensitivity to chemotherapies and aimed at determining if the presence of NLRP3 could predict the response to chemotherapies. The scientific objectives of the project were mostly achieved with some adjustments from the initial proposal. Collaborations within the host institute allowed to set-up alternative measures to bypass technical issues encountered in the scientific program and acquire experimental data to attain the objectives set-up in WP2 and WP3. The compiled data led to the identification of a non-immune function for NLRP3 in genome integrity surveillance and strengthen the concept of a functional link between innate immunity and DNA damage sensing pathways. The release of a research article was one of the main achievements in transfer of knowledge of the RoNDBioCan project, but the data collected during the grant period will also feed at least two or three additional research publications in the coming years. WP1 also delivered a list of NLRP3 partners involved in the response to genotoxic stress, allowing the development of a new research project led by the fellow. The management of the project was conducted under WP4. In WP5, for career development and training, the fellow supervised 2 incoming students and served as a peer reviewer for academic journals. The fellow followed courses and got the certifications necessary to the accomplishment of the research program. The fellow obtained a permanent researcher position at the French National Institute of Health and medical Research (INSERM) and secure funding to conduct (as a PI) a project derived from RoNDBioCan. In WP6, seminars were used to share expertise among the scientific community. The fellow delivered 4 conferences presentations (with 2 international), co-founded a ""science club"" to gather scientists and give them the opportunity to share tools and set-up collaborations. To reach out to the general public, the fellow was invited to give a seminar at a charity event to explain the work carried out by RoNDBioCan and explain the mission of the MSCA. Finally, the fellow raised awareness of the importance of research to young children and their family in a pediatric hospital using playful workshops and with the organization of 2 science fairs. These different actions reflect the positive impact of the MSCA individual fellowship on early career scientists. Considering the transfer of knowledge activities, the publication and the dissemination produced, the overall objectives of the project were achieved.



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Lung cancer is multimodal pathology with high rates of incidence and mortality, but a substantial lack of effective treatment strategies. At the scientific level, RoNDBioCan contributed significantly to european excellence and society in that it has strengthen the knowledge of lung tumorigenesis. Today, the action of current therapies relies mainly on the induction of highly cytotoxic DNA lesions. For this purpose, RoNDBioCan focused on understanding how our cells (healthy and cancer cells) respond to those treatments and especially how NLRP3, an inflammatory protein can modulate the response to DNA damage. The technical difficulties encountered during this MSCA fellowship only highlighted the importance to investigate the molecular mechanisms that direct the emergence and progression of the disease, along with the application of these findings for clinical treatment.
By improving the current knowledge on NLRP3 biology and especially understanding its role in the DNA Damage Response, this project brought to light new connections between two major hallmarks of cancer: inflammation and genomic instability. Through the fellow’s research on NLRP3 function in cancer development, new understandings are emerging on how cells orchestrate the dual function of NLRP3 in immunity and in protecting genome integrity. While this project consists primarily of fundamental research, it carries a beneficial impact regarding lung cancer biology. RoNDBioCan could open avenues for the development of new therapeutic strategies and, in that way, could contribute indirectly to relieve the economic burden of Lung cancer treatment. During the MSCA, the fellow assembled a strong and interesting network of international scientists both in the cancer field and the innate immunity field that are now collaborating on a new research project led by the fellow on NRLP3 regulation and based on the data obtained from RoNDBioCan.
Impact anticipated from the MSCA are increased and improved for the career development of the fellow. She developed competences with many different research technics but also improved her communicating skills by sharing the results from the RoNDBioCan research program to a broad public. The fellow created many workshops and organized main events for hospitalized children and their family at the Pediatric Hematology and Oncology Institute to get them to understand the current research conducted on cancer biology but also to teach them that science can be just fun.
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