Le carcinome hépatocellulaire est un grand problème de santé publique et la troisième de mortalité lié au cancer dans le monde. Il a été démontré qu'au sein des tumeurs se trouve un petite population des cellules cancéreuses avec des propriétés de cellules souches cancéreuses. Elles sont responsables de l'initiation des tumeurs ainsi que de la récidive post-traitement et résistance aux thérapies. Peu de choses sont connues par rapport à la biologie de ces cellules mais l'identification des facteurs favorisant leur existence pourrait conduire vers des nouvelles pistes thérapeutiques.Nous avons trouvé que le facteurs de transcription p73 est surexprimé chez les patients dans les tumeurs du carcinome hépatocellulaire sous forme de deux types d'isoformes, les isoformes complets et les isoformes tronqués. Les isoformes complets sont des suppresseurs de tumeurs et corrèlent avec un meilleur taux de survie alors que les isoformes tronqués agissent comme dominants négatifs de ces premiers et favorisent la récidive post-chirurgie.Les résultats in vitro ont montré que les isoformes tronqués de p73 sont surexprimés dans les cellules souches cancéreuses du carcinome hépatocellulaire et favorisent leur emergence / Hepatocellular carcinoma (HCC) is a major public health problem, being the second most lethal cancer with an increasing incidence around the world. The only approved systemic drug is the multikinase inhibitor Sorafenib, which prolongs patients’ survival by only three months. HCC is refractory to known chemotherapeutic drugs and more than 50% of patients relapse after surgical tumor removal. These phenomena are thought to be due to the existence of a population of poorly differentiated cancer cells, largely known as liver cancer stem cells (CSCs). Recent studies revealed that CSCs activate similar pathways as normal stem cells. They are therefore highly resistant to therapies and are thought to be capable of self-renewal and generation of tumor’s heterogeneous cell mass. The understanding of mechanisms proper to liver CSCs should allow the development of innovative drugs with original mechanism of action against liver CSC, likely to improve patients’ outcome. However, the development of new therapies against HCC is penalized by the limited number of experimental models.According to these current challenges in the field of HCC research, my PhD thesis project covers three main axes: Development of novel models of disease (IMODI consortium)The Innovative Models of Disease (IMODI) consortium is mainly dedicated to the development of innovative experimental models for 7 different types of cancer. Our participation to the project concerned 3 main objectives i) development of HCC patient-derived xenografts ii) development of new HCC cell lines and iii) set up a cryoconservation method of primary human hepatocytes (PHHs) in the aim to employ them in humanizing murine livers. 30 patients planned for HCC tumor resection were recruited and their clinicopathological data were collected. Fresh tumor specimens were subcutaneously xenografted in immune-deficient mice and dissociated for in-vitro tumor cell culture. One tumor led to the development of a moderately differentiated HCC PDX model, as confirmed by histological characterization. Several studies showed the importance of PDX models in drug discovery as they recapitulate the drug-sensitivity patterns seen in patients from which they derive but very few models have been described in the literature for HCC. In vitro, primary HCC cells could be maintained in culture for a limited period of time, in average 30 days. No HCC cell lines developed due to cells entering replicative senescence, as previously described

Les modifications post-traductionnelles de la tubuline sont des cibles attrayantes pour la thérapie du cancer. TTLL12 est impliqué dans la détyrosination de la tubuline, la triméthylation de l’histone H4K20 et le cancer de la prostate. La thèse porte sur les effets de la surexpression de TTLL12 sur ces modifications à différents stades du cycle cellulaire et sur la sensibilité à des agents ciblant les microtubules. Les résultats montrent que TTLL12 affecte ces modifications indépendant du cycle cellulaire et réduit la sensibilité des cellules à paclitaxel. XRP44X est un nouvel inhibiteur de la signalisation Ras-ERK-Elk3. Ses propriétés antitumorigène ont été montré in vitro et dans certaines études in vivo. Le projet de thèse était une continuation des études pré-cliniques sur XRP44X dans des modèles de cancer de la prostate de souris. Les résultats montrent que XRP44X est un inhibiteur efficace de la tumorigenèse et des métastases, ce qui peut être dû à son effet sur Elk3. / Tubulin posttranslational modifications are an attractive target for cancer therapy. TTLL12 isinvolved in tubulin detyrosination, histone H4K20 trimethylation and prostate cancer. The thesis addresses the effects of TTLL12 overexpression on these tubulin and histone modifications at different stages of the cell cycle and on sensitivity to microtubule-targeting agents. The results show that TTLL12 over expression affects tubulin detyrosination and H4K20 trimethylation independently of cell cycle phase and reduces cell sensitivity totaxanes.XRP44X is a novel inhibitor of Ras-ERK1/2-Elk3 signalling and tubulin-binding agent. Itsantitumorigenic properties had been shown in vitro and in initial in vivo studies. The thesis project was a continuation of pre-clinical studies on XRP44X in mouse prostate cancer models. The results show that XRP44X is an effective inhibitor of tumorigenesis and metastasis in prostate cancer, which may be due to its effect on Elk3.