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Xeroderma Pigmentosum Syndrome: a New Model to Study the Role Of Xeroderma Pigmentosum syndrome : A new model to study the role of fibroblasts in the modulation of the innate immune response against cutaneous cancer cells Maria João Gonçalves Maia To cite this version: Maria João Gonçalves Maia. Xeroderma Pigmentosum syndrome : A new model to study the role of fibroblasts in the modulation of the innate immune response against cutaneous cancer cells. Cancer. COMUE Université Côte d’Azur (2015 - 2019), 2019. English. NNT : 2019AZUR4037. tel-03000465 HAL Id: tel-03000465 https://tel.archives-ouvertes.fr/tel-03000465 Submitted on 11 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE DE DOCTORAT Le syndrome Xeroderma Pigmentosum Un nouveau modèle pour l’étude du rôle des fibroblastes dans la modulation de la réponse immunitaire innée contre les cellules cutanées cancéreuses. Maria João GONÇALVES MAIA Institut de Recherche sur le Cancer et le Vieillissement, Nice Présentée en vue de l’obtention Devant le jury, composé de : du grade de docteur en Dr. Véronique Braud, President, IPMC, Valbone Interactions moléculaires et Pr. Marie-Dominique Galibert, Rapporteur, IGDR, Rennes cellulaires d’Université Côte d’Azur Pr. Alain Sarasin, Rapporteur, IGR, Paris Dirigée par : Thierry Magnaldo Pr. Alexander Steinle, Examinateur, IMM, Frankfurt Soutenue le : 14 juin 2019 This page was intentionally left bank 1 Acknowledgements First, I would like to express my sincere gratitude to all of the members of my thesis scientific committee for accepting to evaluate my PhD work. I’m honored to have Dr. Véronique Braud as the president of the jury, Professor Marie-Dominique Galibert-Anne as a reporter, Professor Alain Sarasin also as a reporter and Professor Alexander Steinle as an examiner. My sincere thanks to Thierry, my thesis supervisor, for giving me the opportunity to carry out the present thesis work, for sharing with me his scientific knowledge, and for granting me the freedom to explore the different research paths presented in this manuscript. I always felt how much you appreciated my work, all the confidence you had in my results and the genuine enthusiasm you expressed with the advances of this thesis project. I am truly grateful for your trust. It gave me confidence, courage, and the certainty that I could be a good researcher in the future if I chose this path. For this, I thank you. Véronique, in addition to accepting to be the president of my thesis committee, I would like to thank you for committing so much of your time to this project during the past 3 and a half years. Everything I know about immunity I learned from you. Your dedication and enthusiasm towards this project inspired, encouraged, and gave me the motivation and strength to continue. I’m grateful that I had the opportunity to work with you. It was a real pleasure and an enriching professional experience that I won’t forget. Finally, thank you for the invaluable contribution you gave to this manuscript. Yannick, thank you for the intellectual contribution you gave to this work since the beginning. Your interest and all our scientific (and nonscientific) discussions helped me enormously in writing this project and concluding it. Thank you for teaching me how to perform most of the laboratory techniques I used during my thesis, how to improve experimental conditions and for always taking the time to review my writings. I would like to also thank you for your friendly support. Especially for all the times you gave me the last chocolate you had in your drawer and for always caring for me and my well being. I couldn’t have done this without you. Lastly, thank you for all of the knowledge and good energy you put into improving this manuscript and for your kind corrections. A special thanks is also needed for Sabine. I’m sure that not many people truly realize how important and fundamental your work is to our Institute. You are always the first person we call when we smell something odd, when we hear something unusual, when we see something strange. When we have a problem with door locks, with freezers, with incubators. When we need to buy a particular product, to move large equipment or to change the filter of our PSM. I 2 really could write a dissertation containing only the multitude of the things that you do for us on a daily basis. The most important though, is your availability to take the time to listen to us and our problems. You were a constant and reassuring presence during these past years and I know we will keep in touch for years to come. Thank you. Margot and Julia “mes copinettes”! The first acknowledgement lines I wrote were actually to thank you two! Not only for our surrealistic discussions that reassured me that I wasn’t alone in my thinking but also for your friendship, for your continuous support, and for making my days in the Pasteur tower so much fun! Finally, thank you for running with me our incredible Instagram account @lavieaulabo. I will always cherish the friendship we have created. I lOvE yOu! I also want to thank all the former members of the laboratory especially Sahar, Sophie and Miguel. Thank you for your support and the assistance you gave towards this work. Valérie and Nicolas, thank you for always taking the time to help me deal with the incredibly complex work of orders and shipments. I appreciate all of your help. To the people of the second floor of the Pasteur tower, thank you for your genuine concern for my wellbeing and for all of the fun and interesting discussions we had over these past years that helped me growth as a researcher and most importantly as a person. A particular thanks also goes to Marina Shkreli that generously let me use one of her team’s desks for almost a year now, and to all of Paquis team, for the laughter and good moments we shared together. To my family, the ones with whom I share a bloodline and the ones with whom I chose to share life with. For them, I’m the cousin, the niece, the godmother, the best friend, the chief, the lucky one, the fearless... For me, they are the reason I wake up happy every morning. Having you in my life has made this path a lot easier. Thank you for your love and friendship, for all of your understanding that I am a bit too far away to be able to see you as much as I would like and for coming to visit as much as you can. I feel blessed to have you in my life. Ivo, thank you for your support, encouragement and understanding of my goals and my aspirations. Your love is a blessing and has been my major source of strength. Without your help, I would not have been able to complete much of what I have done and become who I am today. Thank you for being with me every single day and for never letting me feel lonely in this solitary journey. There are no words to express how much I value and love you. Aos meus pais, meus exemplos maiores, que são a constante da minha vida, a presença de todas as horas e a certeza de que o Amor é o unico que importa. Obrigada. 3 Résumé de la thèse L’étiologie des cancers cutanées est liée à des mutations génétiques résultant de l’exposition aux rayonnements ultraviolets (UV) émis par le soleil. La propagation des cellules cancéreuses dépend aussi des interactions avec les cellules présentes dans le microenvironnement circulant, notamment des fibroblastes associés au cancer (FAC) et des cellules immunitaires. Xeroderma pigmentosum (XP) est une maladie génétique qui comprend 7 groupes de complémentation génétique (XP-A à XP-G). Les patients XP présentent une déficience du mécanisme de réparation des lésions de l’ADN provoquées par les UV. Ces patients sont susceptibles au développement précoce de très nombreux cancers cutanées. XP-C est le groupe de complémentation le plus représenté en Europe. Chez ces patients, les carcinomes spino-cellularies (CSC) sont plus fréquents que les carcinomes baso-cellulaires (CBC) (taux 5 : 1). Les CSC ont un potentiel métastatique plus élevé que les CBC. Des travaux précédents ont suggéré que la réponse immunitaire chez les patients XP pouvait être altérée, incluant un déficit de l’activité cytolytique des cellules Natural Killer (NK) et une diminution du nombre des lymphocytes T circulants. L’objectif central de cette thèse était, d’identifier des facteurs du microenvironnement impliqués dans la progression des cancer cutanées agressifs, en prenant comme modèle de susceptibilité au cancer, des cellules de patients XP-C. Une analyse transcriptomique comparant les fibroblastes WT et des patients XP-C a permis d’identifier que CLEC2A, un ligand activateur du récepteur NKp65 des cellules NK, est exprimé par les fibroblastes WT mais pas par les fibroblastes XP-C. Nos travaux ont pu montrer une diminution du niveau d’expression de CLEC2A au cours de la sénescence réplicative ; une absence dans les FAC et dans les CSC et que, des facteurs solubles secrétés para les CSC diminuent l’expression de CLEC2A.
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