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Rôle Des Récepteurs Aux Oxystérols Lxrs (Liver X Receptors) Dans La Dissémination Métastatique Du Cancer De La Prostate Anthony Alioui

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Rôle Des Récepteurs Aux Oxystérols Lxrs (Liver X Receptors) Dans La Dissémination Métastatique Du Cancer De La Prostate Anthony Alioui Rôle des récepteurs aux oxystérols LXRs (Liver X Receptors) dans la dissémination métastatique du cancer de la prostate Anthony Alioui To cite this version: Anthony Alioui. Rôle des récepteurs aux oxystérols LXRs (Liver X Receptors) dans la dissémination métastatique du cancer de la prostate. Sciences agricoles. Université Blaise Pascal - Clermont-Ferrand II, 2016. Français. NNT : 2016CLF22780. tel-01587657 HAL Id: tel-01587657 https://tel.archives-ouvertes.fr/tel-01587657 Submitted on 14 Sep 2017 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. UNIVERSITÉ BLAISE PASCAL UNIVERSITÉ D’AUVERGNE N° D. U. 2780 ANNEE : 2016 ECOLE DOCTORALE DES SCIENCES DE LA VIE, SANTÉ, AGRONOMIE, ENVIRONNEMENT N° d’ordre : 709 Présentée à l’Université Blaise Pascal pour l’obtention du grade de DOCTEUR D’UNIVERSITÉ Spécialité : Physiologie et Génétique Moléculaire (Endocrinologie Moléculaire et Cellulaire) Présentée et soutenue publiquement par Anthony ALIOUI Le 19 décembre 2016 Rôle des récepteurs aux oxystérols LXRs (Liver X Receptors) dans la dissémination métastatique du cancer de la prostate Rapporteurs : Dr. Muriel LE ROMANCER-CHERIFI, UMR 1052 CRCL, Lyon Pr. Vincenzo RUSSO, Ospedale San Raffaele, Milan Examinateurs : Dr. Véronique COXAM, UMR 1019 UNH Clermont-Ferrand Pr. Florence CALDEFIE-CHEZET, UMR 1019 UNH Clermont-Ferrand Pr. Noam ZELCER, Academic Medical Center, Amsterdam. Directeur de thèse : Dr. Silvère BARON, UMR GReD, Clermont-Ferrand Laboratoire UMR GReD CNRS-INSERM-Clermont Université Rôle des récepteurs aux oxystérols LXRs (Liver X Receptors) dans la dissémination métastatique du cancer de la prostate. La prise en charge clinique du cancer de la prostate est complexe. L’identification des éléments et altérations génétiques impliqués dans la progression de la maladie est donc capitale. Les altérations métaboliques représentent des changements clés vis-à-vis de la croissance de la cellule tumorale. Parmi ces modifications, l’augmentation du métabolisme du cholestérol est fréquemment observée au sein de différentes pathologies tumorales, dont le cancer de la prostate. En lien, des études épidémiologiques associent l’enrichissement du cholestérol avec une augmentation de l’incidence, la progression et l’agressivité de la maladie. Les récepteurs nucléaires aux oxystérols LXRs (Liver X Receptors) constituent des régulateurs majeurs de l’homéostasie du cholestérol, et différents travaux récents mettent en évidence leur potentiel anti-prolifératif et pro-apoptotique dans différentes lignées cellulaires du cancer de la prostate. En association ces travaux de thèse démontrent, dans un modèle murin d’adénocarcinome prostatique PTEN-dépendant, une activation endogène et constitutive des LXRs en réponse à une augmentation du taux de cholestérol intra-prostatique, principale source des ligands oxystérols. L’invalidation additionnelle des LXRs dans ce contexte conduit à une augmentation importante de la croissance tumorale et à la dissémination métastatique, notamment expliquée par une dérégulation de la voie du TGFβ et de la transition épithélio-mésenchymateuse. L'ensemble de ces résultats place les LXRs comme des cibles thérapeutiques prometteuses. Mots clés : Cancer, Prostate, LXRs, Cholestérol, Métabolisme, PTEN. LXRs (Liver X Receptors) involvement during prostate cancer metastatic dissemination. Clinical management of prostate cancer is complex. The identification of elements and genetic alterations involved in disease progression is therefore crucial. Metabolic alterations represent key modifications during tumor cell growth. Among these modifications, cholesterol metabolism increase is frequently observed in various tumor pathologies, including prostate cancer. Related, epidemiological studies associate cholesterol enrichment with an increase of disease incidence, progression and aggressiveness. LXRs (Liver X Receptors) belong to the nuclear receptors superfamily and represent major sensors and regulators of cholesterol homeostasis. Recent studies have demonstrated their anti- proliferative and pro-apoptotic potential in various prostate cancer cell lines. In link, this thesis work demonstrate endogenous and constitutive activation of LXRs in a murine model of PTEN-dependent prostate adenocarcinoma in response to an increase of intra-prostatic cholesterol, the major source of oxysterol ligands. The additional invalidation of LXRs in this context leads to a significant increase of tumor growth and metastatic dissemination, notably explained by a TGFβ pathway deregulation, concomitant with epithelial-mesenchymal transition process increase. All of these results define LXRs as promising therapeutic targets. Key words : Cancer, Prostate, LXRs, Cholesterol, Metabolism, PTEN. Remerciements Je tiens tout d’abord à remercier l’ensemble des membres de mon jury de thèse : le Docteur Muriel Le Romance-Chérifi, le Professeur Vincenzo Russo, le Docteur Véronique Coxam, le Professeur Florence Caldefie-Chézet et le Professeur Noam Zelcer d’avoir accepté d’évaluer mon travail de thèse. Je remercie tous les membres de l’équipe « LXR » que j’ai côtoyé tout au long de ces années de thèse : Silvère, Jean-Marc, Laurent, Amalia, David, Cyrille, Aurélie, Allan, Amandine, Lauriane, Betty, Laura, Guy, Hugues, Julie, Salwan, Marine. Leur accueil fût chaleureux et leurs conseils très précieux. Je tiens tout particulièrement à remercier Silvère pour m’avoir fait confiance pendant ces trois années. Merci de m’avoir habilement inculqué toutes les qualités nécessaires à mener un projet de thèse dans de bonnes conditions, qualités qui continueront de m’aider tout au long de ma carrière. Merci d’avoir toujours su trouver des solutions et m’épauler dans les moments difficiles du projet, mais également pour m’avoir laisser beaucoup d’autonomie et d’initiatives l’instant venu. J’admire ta qualité de réflexion et ta culture scientifique, mais ne prends pas la grosse tête quand même « mon garçon ». Je remercie Jean-Marc pour m’avoir accueilli dans l’équipe et « sorti du ruisseau ». Dans un certain sens tu as raison, ces trois années passées avec vous, avec toi, m’ont beaucoup enseigné. Tu as toujours été de bon conseil et rassurant. Je pense que tu resteras à mes yeux une personne charismatique, et j’espère que tu profiteras bien de ton échappée italienne (l’école doctorale est maintenant en berne). J’attends toujours la blague de la figue au fait... Merci à Laurent, le Grand Sage. Comme Jean-Marc, tu as été de très bon conseil. Tes remarques sont toujours diablement pertinentes, ta culture scientifique vaste, et tu sauras éternellement rassurer les étudiants en détresse grâce à ton calme olympien. Je remercie Julie que je n’ai pas eu la chance de côtoyer assez longtemps, qui s’est très bien occupée de moi dès mon arrivée, et sans qui le projet ne serait pas aussi aboutit à l’heure actuelle. Je remercie Allan, tu m’as toujours apporté ton aide en temps voulu, enfin quand tu n’étais pas occupé avec un stagiaire quoi. J’espère que la fin de ta thèse se déroulera bien, tu le mérites amplement. Merci à Laura. Ton intérêt pour le projet, ta présence et tes questions ont su m’apporter un élan de réflexion, de force et de motivation lors de ma dernière année de thèse. J’espère que ton doctorat se déroulera aussi bien que la mien, enfin tout du moins si tu le termines vivante mademoiselle catastrophe. Nous n’avons passé qu’une année ensemble mais je pense que nous avons beaucoup partagé. Ne te décourage pas face aux moments difficiles, ton travail finira par payer, enfin si tu fais pas exploser le labo. Je remercie Aurélie, qui a su me régaler les papilles pendant ces 3 années. Ta bonne humeur communicative et tes talents de cuisinière ont été deux gros atouts non négligeables au sein de l’équipe. Betty, tout comme Aurélie, ta bonne humeur a souvent été communicative et j’espère que tout se passe bien pour toi au pays du Jazz et des Poneys. Cyrille, je pense que tes talents d’auteur ne sont plus à démontrer. Après trois années passées à tes côtés, je suis toujours autant surpris par ton sens de l’imagination et tes boutades recherchées, enfin quand je les comprends ! Je remercie Amandine R, le trait d’union. L’école buissonnière Lyonnaise fût fort sympathique lors de notre balade au zoo. Merci à toi monsieur le double Docteur Maqdasy. Ta présence au labo le mercredi est à chaque fois une bouffée d’air et un sas de décompression. Et oui, tu en racontes des bêtises... entre deux prescriptions médicales par téléphone. Merci à Amalia, entre fumeurs nous avons su nous entraider lors de ces trois années, il est temps que j’arrête. Je remercie David pour ses remarques souvent pertinentes sur la conduite de mon projet de thèse lors de nos réunions d’équipe. Merci à Guy, principale personne à me faire de la concurrence le week-end au laboratoire. En effet depuis ton retour au sein de notre équipe, j’ai plutôt tendance à réserver les salles de culture cellulaire ou de western blot. Tu es quelqu’un de courageux et tu ne te démoralises jamais, tes questions sont toujours justifiées, et tes conseils ont su faire avancer mon projet, mais tu chantes un peu trop fort Monsieur Ouedraogo ! Je remercie Lauriane. J’espère que ton post-doctorat s’achèvera dans les meilleures conditions, que la perspective de carrière que tu comptes réaliser se déroulera bien. On garde contact au cas où j’aie un comptage cellulaire un de ces jours, je sais que tu me feras ça en deux deux (non ne pleurs pas). Merci à Olivier, pour m’avoir rassasié de ses délicieuses viennoiseries chaque semaine. Je te souhaite une bonne continuation, et bon courage pour la rédaction de ton manuscrit.
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