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Induction De La Voie IFN/STAT1 Dans Le Cancer Du Sein Sous Chimiothérapie

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Induction De La Voie IFN/STAT1 Dans Le Cancer Du Sein Sous Chimiothérapie THESE DE DOCTORAT DE L’UNIVERSITE PARIS DESCARTES Ecole doctorale Bio Sorbonne Paris Cité (BioSPC) Discipline : Sciences de la vie Spécialité : Biologie cellulaire Induction de la voie IFN/STAT1 dans le cancer du sein sous chimiothérapie. Etude mécanistique. Présentée par Julie GASTON Thèse CIFRE dirigée par le Dr Vincent Goffin Soutenue le 5 Juillet 2016 Devant le jury composé de : Madame le Professeur Emmanuelle Charafe-Jauffret Rapporteur Monsieur le Docteur Hichem Mertani Rapporteur Madame le Docteur Sandra Pellegrini Examinateur Monsieur le Docteur Thierry Dubois Examinateur Monsieur le Docteur Vincent Goffin Directeur de thèse Monsieur le Docteur Stefano Cairo Tuteur de thèse Résumé Induction de la voie IFN/STAT1 dans le cancer du sein sous chimiothérapie. Etude mécanistique. Le cancer du sein est le cancer le plus fréquent chez la femme. Malgré la chimiothérapie, certaines patientes ont une réponse incomplète et récidivent quelques années plus tard. Le but de ce travail était d’étudier les mécanismes moléculaires mis en place par les cellules tumorales en réponse aux traitements et leur rôle éventuel dans la récidive. La modélisation de ces événements a d’abord été réalisée grâce à des modèles expérimentaux appelés PDX (pour patient derived xenograft) impliquant la greffe de tumeurs de patientes chez la souris immunodéficiente. Une analyse transcriptomique a permis de mettre en évidence, au sein des PDXs qui répondent à la chimiothérapie, la surexpression précoce de gènes cibles de la voie interféron (IFN)/STAT1, suggérant que cette signature moléculaire pourrait être utilisée comme biomarqueur prédictif de la réponse initiale au traitement. Cette signature persiste néanmoins dans les cellules tumorales résiduelles, suggérant qu’elle pourrait également avoir un rôle dans la récidive observée pour l’ensemble des PDX étudiées. L’analyse fonctionnelle de cette signature IFN/STAT1 a été réalisée in vitro, en traitant diverses lignées de cancer du sein par du mafosfamide, principe actif d’une chimiothérapie classique induisant des dommages à l’ADN. Nos résultats montrent que, sous chimiothérapie, certaines lignées (dont les cellules MFC7) sont capables d’exprimer des IFNs de type I conduisant à l’activation autocrine/paracrine de la voie IFN/STAT1. Une étude mécanistique a mis en évidence l’implication du détecteur de l’ADN STING (stimulator of IFN genes) en amont de la production d’IFN, comme cela a été bien décrit dans des cellules immunitaires en présence de pathogènes. Nous avons montré que l’inhibition individuelle de l’expression de différents acteurs de la voie STING/IFN/STAT1 potentialise l’effet de la chimiothérapie, impliquant cette cascade dans la résistance au traitement. En résumé, notre travail suggère que l’activation de la voie STING/IFN/STAT1 dans les cellules tumorales mammaires traitées par chimiothérapie pourrait jouer un double rôle : biomarqueur de la réponse dans un premier temps, puis acteur de résistance dans un second temps. Ce travail ouvre de nouvelles perspectives pronostiques et thérapeutiques pour la prise en charge du cancer du sein. Mot clés : cancer du sein, PDX, chimiothérapie, récidive, interféron, STING, STAT1 Abstract Induction of the IFN/STAT1 pathway in breast cancer after chemotherapy. Mechanistic study. Breast cancer is the most frequent cancer in women. Despite chemotherapy, tumor response is often incomplete, and relapse is frequently observed. The aim of this work was to analyze the molecular mechanisms triggered in breast cancer cells in response to chemotherapy. These events were modeled using breast cancer patient-derived xenografts (PDXs), i.e. samples of human tumors engrafted into immunodeficient mice. Transcriptomic analysis highlighted precocious induction of the interferon (IFN)/STAT1 pathway in response to chemotherapy only in tumors responding to treatment, suggesting that this molecular signature could be used as a biomarker of the initial response. The activation of this pathway persisted in residual tumor cells, suggesting that it could also play a role in cancer recurrence observed in all PDX models that we investigated. Functional deciphering of the IFN/STAT1 pathway was performed in vitro by stimulating breast cancer cell lines with mafosfamide, the active principle of a classical chemotherapy inducing DNA damage. In some cell lines, e.g. MCF-7 cells, this treatment triggered the upregulation of type I IFN expression leading to cell-autonomous activation of the IFN/STAT1 signaling pathway. A mechanistic study revealed the involvement of the DNA sensor STING (stimulator of IFN genes) upstream of the IFN production, mimicking what happens in immune cells facing pathogen infection. Individual silencing of various actors of the STING/IFN/STAT1 pathway potentiated genotoxic treatment efficacy, indicating that this cascade may be involved in tumor resistance to treatment. In summary, our study suggests that cell-intrinsic activation of STING/IFN/STAT1 pathway in response to chemotherapy could play a dual role: first, it may be used as a predictive biomarker of initial response; second, it may act as a resistance mechanism to treatment. This work opens new prognostic and therapeutic perspectives for the clinical management of breast cancer. Keywords: breast cancer, PDX, chemotherapy, recurrence, interferon, STING, STAT1 Remerciements Au terme de ce travail de thèse, je tiens à exprimer mes sincères remerciements aux membres de mon jury. Je remercie Madame le Professeur Emmanuelle Charafe­Jauffret et Monsieur le Docteur Hichem Mertani d’avoir accepté d’être les rapporteurs de ce travail de thèse et d’avoir pris le temps d’évaluer mon manuscrit. Je remercie également Madame le Docteur Sandra Pellegrini et Monsieur le Docteur Thierry Dubois, mes examinateurs, qui je l’espère, prendront plaisir à lire ce travail. Je tiens vraiment à remercier toutes les personnes qui ont participé à ce projet de thèse que j’ai toujours voulu réaliser après mes études d’ingénieur. Je voudrais remercier tout particulièrement Vincent Goffin, mon directeur de thèse. Grâce à vous, j’ai découvert le monde académique et ses chercheurs passionnés. Vous m’avez donné le réel sentiment d’appartenir à une équipe et nos échanges m’ont toujours énormément apporté sur le domaine scientifique mais aussi personnel. Toujours à l’écoute, vous avez pris le temps de m’expliquer, de discuter pour avancer ensemble, et j’ai beaucoup apprécié cela. Je vous remercie également pour toute la confiance que vous m’avez accordée. Je remercie XenTech, Jean­Gabriel Judde et Pascal Leuraud pour m’avoir donné l’opportunité de réaliser cette thèse en collaboration avec le laboratoire de Vincent Goffin. Ces quatre années à Xentech m’ont permis de découvrir différentes phases que peut vivre une entreprise. Je remercie Stefano Cairo pour m’avoir encadrée à XenTech. Tu m’as permis de développer un esprit critique sur l’analyse des résultats et tu as aussi contribué à forger ma personnalité. Merci aussi à Olivier Deas pour ces nombreux conseils scientifiques. Je tiens aussi à remercier Marie­France Poupon qui m’a toujours donné des conseils scientifiques judicieux et pertinents tout au long de ma thèse et qui m’a fait de précieuses remarques dans la relecture de ce manuscrit. Aux « Xentech-iens » : Vanessa, merci pour tous ces fous rires au labo, pour ton soutien moral aussi, lorsque je me suis rendu­compte que « le monde des bisounours » n’existait pas. Vivement les prochains afterworks ! Combien de paille dans le prochain mojito ? Et ne t’inquiète pas, ta «fashion coach» continue de surveiller ton style ! Et celui de mon futur filleul !! ;) Laura, je te décerne le titre de la meilleure stagiaire. Merci pour l’implication que tu as donnée dans ton travail, en espérant que les Western Blot ne te jouent plus de mauvais tours !! ;) Sophie, Bénédicte et Enora, petite équipe de R&D mais solide, j’espère que nous continuerons à former une belle équipe ! Léa et Delphine, j’ai beaucoup apprécié le trio de choc que nous avons formé lors des congrès. Léa, j’espère que tu viendras me montrer des recettes thermomix à la maison! Myriam et Delphine, merci pour vos conseils et votre implication pour mes études in vivo. Marianna et Valeria, vous ne voudriez pas rester à XenTech plus longtemps ? J’adore ce nouveau bureau ! Merci à « mon bureau des plaintes » (Josi, Léa et Vanessa) qui se transforme toujours en « bureau des rires » !!! Enfin, je remercie tous les autres Xentech­iens pour votre bonne humeur. Qui d’entre nous gagnera l’Euro ? 1 Aux EX- Xentech-iens : Marie­Emmanuelle, ton départ a vraiment laissé un vide. Tu as été une excellente maitre de stage et tu as su me transmettre ta passion. Tu es un exemple pour moi. Merci pour ton soutien, ta rigueur scientifique, ta patience. Grâce à toi, je n’ai que des compliments sur mes western blot ! ;) Arnaud, mon souvenir le plus fort est la qPCR et ces plaques 384 puits… traumatisée à jamais… merci !!! Et pour finir : MIAOUUUUU !!!! Evgeniya, ton calme à toute épreuve est impressionnant. J’espère que l’on aura l’occasion d’aller danser les sévillanes ensemble très vite! Gaël, je crois que c’est grâce à toi que mon CV est apparu dans les bureaux de Xentech donc un GRAND merci !! Ludovic, merci pour ta bonne humeur, j’espère que l’on redansera le rock à la Nouvelle­Orléans ou ailleurs ! A la pépinière : Merci à Nathalie, pour ta bonne humeur et nos midis potin en compagnie de Pauline, Maud, Céline, Fabien, Estelle (Pipiche), Carole, Didier, Marie­Noëlle, Erwan. Pauline, quelle chance tu as
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