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La Protéine HSP110: Rôle Dans Le Développement Tumoral Et Sur L La protéine HSP110 : rôle dans le développement tumoral et sur l’immunogénicité du cancer colorectal Kevin Berthenet To cite this version: Kevin Berthenet. La protéine HSP110 : rôle dans le développement tumoral et sur l’immunogénicité du cancer colorectal. Médecine humaine et pathologie. Université de Bourgogne, 2015. Français. NNT : 2015DIJOS059. tel-01289793 HAL Id: tel-01289793 https://tel.archives-ouvertes.fr/tel-01289793 Submitted on 18 Mar 2016 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. UNIVERSITE DE BOURGOGNE U.F.R. de MEDECINE Ecole Doctorale Environnements - Santé - STIC THESE Présentée pour l’obtention du titre de DOCTEUR DE L’UNIVERSITE DE BOURGOGNE Discipline : Science et Vie LA PROTEINE HSP110 : ROLE DANS LE DEVELOPPEMENT TUMORAL ET SUR L’IMMUNOGENICITE DU CANCER COLORECTAL Présentée et soutenue publiquement par Kévin BERTHENET Le 3 décembre 2015 Membres du jury : Dr Palma Rocchi…………………………………………………………………..Rapporteur Dr Toby Lawrence………………………………………………………………...Rapporteur Dr Alex Duval……………………………………………………………………Examinateur Dr Gaetan Jego……………………………………………………..…Co-encadrant de thèse Dr Carmen Garrido………………………………………………………..Directeur de thèse Pr Evelyne Kohli……………………………………………………………………..Président 1 Résumé Notre équipe étudie les HSP, et notamment HSP110. Les HSP sont des chaperons impliqués dans le repliement des protéines nouvellement synthétisées et dénaturées. Les HSP sont surexprimées lors des stress et participent à la survie des cellules par leurs propriétés anti- apoptotiques et anti-agrégations. HSP110 est surexprimée dans le cancer colorectal et est associée à un mauvais pronostic. L’expression d’un mutant d’HSP110, nommé HSP110ΔE9, a été mise en évidence dans les cancers colorectaux de type MSI. Celui-ci y agit comme un dominant négatif, en se liant à HSP110 et en inhibant ses fonctions. Son expression sensibilise les cellules cancéreuses à la chimiothérapie et est associée à un bon pronostic chez les patients. Je me suis tout d’abord intéressé au rôle d’HSP110 dans la régulation de la voie oncogénique STAT3. Son activation est en effet associée à un mauvais pronostic, par l’induction de gènes impliqués dans la prolifération et la survie. La protéine HSP110 favorise la prolifération des cellules colorectales cancéreuses à travers cette voie. HSP110ΔE9 en revanche l’inhibe. Je me suis ensuite intéressé au rôle d’HSP110 sur la polarisation des macrophages dans le cancer colorectal. Celle-ci peut être sécrétée par les cellules cancéreuses et induit une polarisation pro-tumorale des macrophages. HSP110ΔE9, en bloquant la sécrétion d’HSP110, conduit en revanche à une polarisation pro-inflammatoire. L’effet d’HSP110 sur la polarisation implique le récepteur TLR4. L’ensemble de ces résultats montrent le rôle d’HSP110 dans la progression tumorale. HSP110 apparaît comme une cible thérapeutique dans le traitement du cancer colorectal. 2 Abstract Our team studies HSPs, including HSP110. HSPs are chaperones involved in the folding of newly synthesized and denatured proteins. HSPs are overexpressed under stress conditions and are involved in cell survival thanks to their anti-apoptotic and anti-aggregation functions. HSP110 is overexpressed in colorectal cancer and is associated with a poor prognosis. The expression of a mutant HSP110, named HSP110ΔE9, has been shown in MSI colorectal cancer. This one was shown to act there as a dominant negative, by binding HSP110 and inhibiting its functions. Its expression sensitizes cancer cells to chemotherapy and is associated with a better prognosis for patients. I was first interested in HSP110 role in regulating the oncogenic STAT3 pathway. Its activation is associated with a poor prognosis, as it induces the transcription of genes involved in proliferation and survival. HSP110 favors colorectal cancer cell proliferation through this pathway. Conversely, HSP110ΔE9 inhibited it. I then focused on the role of HSP110 on macrophage polarization in colorectal cancer. HSP110 can be secreted by cancer cells and induces a pro-tumoral macrophage polarization. In contrast, HSP110ΔE9, by inhibiting HSP110 release, leads to a pro-inflammatory polarization. HSP110 effect on macrophage polarization involve the TLR4 receptor. All these results show HSP110 role in tumor progression. HSP110 appear as a therapeutic target in the treatment of colorectal cancer. 3 Remerciements Je tiens tout d’abord à remercier vivement les membres de mon jury, qui m’ont fait l’honneur de juger ce travail malgré leurs obligations professionnelles. Je remercie le Docteur Toby Lawrence et le Docteur Palma Rocchi pour avoir accepté d’être rapporteur de ce travail. Je remercie également le Docteur Alex Duval pour avoir accepté d’en être un examinateur et pour sa collaboration avec notre équipe sur ce projet de thèse. Je remercie le Professeur Evelyne Kohli pour avoir accepté d’être la présidente de mon jury. Je remercie la Ligue contre le Cancer et la Fondation pour la Recherche Médicale pour avoir financé ma thèse. Je remercie le Docteur Carmen Garrido pour m’avoir accueilli au sein de son équipe au cours de ces 5 années. Merci pour votre enthousiasme et pour avoir dirigé ma thèse! Merci également pour m’avoir permis de participer à différentes revues scientifiques et au congrès à Washington! Je remercie le Docteur Gaëtan Jego pour m’avoir encadré depuis mon arrivée dans le laboratoire. Merci pour ta gentillesse et pour m’avoir formé à de nombreuses techniques! Merci pour m’avoir fait confiance dans la réalisation des expériences et pour m’avoir permis de participer à différents congrès! Je remercie le Docteur Dominique Thuringer avec qui j’ai pu travailler au cours de ma thèse. Ces travaux ont été très enrichissants pour moi! Je te remercie également pour les nombreux gâteaux que tu as apportés! 4 Je remercie tous les membres, passés ou présents, de l’équipe Garrido. Merci tout simplement pour tout Olivier! Merci pour tous les moments que l’on a passées ensemble (certaines soirées resteront inoubliables!), les discussions (sérieuses ou non!) et les conseils que tu m’as apportés, dans tous les domaines! Grâce te soit rendue pour tout cela! Je te souhaite en tout cas bon courage pour cette dernière année, mais également bonne chance dans l’encadrement de ta petite équipe! Merci Christophe pour tous les bons moments, ainsi que pour toutes les conversations complètement barrées, que l’on a eus! Il est maintenant temps pour moi de partir (mais pas pour Nonolulu malheureusement.. !), c’est désormais toi le boss de notre sous-groupe! Je te souhaite en tout cas bon courage pour la suite, mais je ne m’inquiète pas! Je resterai toujours impressionné par tout ce que tu peux faire (et tout ce qui peut t’arriver !) en seulement une journée! Merci Pierre-Simon, tu es vraiment pour moi un exemple à suivre! Merci Julien! Je me souviendrai toujours du moment où l’on a entendu pour la première fois ton rire particulier au RU. J’étais tout simplement mort de rire! Je te remercie uniquement par politesse Guillaume B…..! Je plaisante, t’inquiètes! Merci Philippe pour ta gentillesse! Merci Alexandre pour ta bonne humeur au quotidien! Merci pour m’avoir fait découvrir la culture brésilienne. Merci également pour m’avoir appris à jouer aux échecs, même si je suis un peu déçu de ne pas avoir réussi l’exploit de te battre une nouvelle fois! Merci Guillaume M pour ta gentillesse, je te souhaite en tout cas bon courage, c’est la dernière ligne droite! Merci Marine pour ta gentillesse! Je resterai toujours surpris de la vitesse à laquelle apparaît ton sourire (comme par magie ?) à la vue de la gastronomie américaine! Merci Nicolas pour la bonne humeur que tu apportes au labo, malheureusement qu’une semaine sur deux! Merci Sébastien C pour le temps passé pour mes images d’immunofluorescence! J’espère que tu me préviendras lorsque tu auras mis au point ton fameux virus Zombie, afin que je puisse me préparer! Merci à toi Guillaume C pour m’avoir autant fait rire! Merci Jessica pour l’organisation des différentes sorties de labo! Merci à toi Renaud pour ta gentillesse. Merci Sarah pour ta bonne humeur et pour nos discussions sur les séries! Je suis fier d’être ton étudiant préféré! Merci également pour m’avoir formé à l’expérimentation animale! Merci Buhran pour l’animation que tu apportes dans le laboratoire! Merci Victor de me rappeler de temps en temps mon fameux adage « la science ça ne peut que marcher !! » que j’ai 5 tendance à oublier ces derniers temps! On attend encore les glaçons Geoffrey! Merci également à Oleg et Anastasia. Merci Thibault pour ta bonne humeur ! Bon courage avec tous tes projets!! Merci à toi Andreï pour les conseils que tu m’as apportés en fin de thèse! Merci Margaux pour ta gentillesse! Merci également pour l’organisation du nettoyage de notre box, et parfois même le rangement de ma paillasse…! Tu es un peu la fée du logis de notre équipe! Merci Antoine pour ton humour un peu décalé! Merci Nathalie pour ton énergie et ta bonne humeur. J’espère que mon entretien pour un stage postdoctoral à Milan se concrétisera afin que je puisse découvrir la culture italienne! (et qu’elle ne se résumera pas à pizza et pates..!) Merci à Sébastien M, Anne Laure, et Guillaume W pour m’avoir accueilli chaleureusement à mes tout débuts dans le laboratoire. Merci Sébastien pour m’avoir formé à la culture cellulaire et autres techniques de laboratoire (Mais qu’est-ce que c’était galère la machine à hypoxie!).
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