Characterization of cellular 3D models of chordoma and evaluation of a radiosensitizing approach ; Validation de modèles 3D de chordome et preuves de concept in vitro d'une stratégie radiosensibilisante
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E-Book
Titel:
Characterization of cellular 3D models of chordoma and evaluation of a radiosensitizing approach ; Validation de modèles 3D de chordome et preuves de concept in vitro d'une stratégie radiosensibilisante
Erschienen:
[Erscheinungsort nicht ermittelbar]: HAL CCSD, 2021
Sprache:
Französisch
Entstehung:
Hochschulschrift:
Dissertation, HAL CCSD, 2021
Anmerkungen:
Beschreibung:
Chordomas are rare slow growing tumors of the axial skeleton. These tumors are locally aggressive, refractory to conventional therapies, and currently untreatable. Radical surgery and radiations remain the first-line treatments. Despite these aggressive treatments, chordomas often recur and second-line treatment options are limited. The mechanisms underlying chordoma radioresistance remain unknown, although several radioresistant cancer cells have been shown to respond favorably to aldehyde dehydrogenase (ALDH) inhibition. The study of chordoma has been delayed by small patient cohorts and few available models due to the scarcity of these tumors. We thus determined i) the transcriptomic signature of a cohort of 13 chordomas samples by RNA sequencing; ii) created cellular 3D models of chordoma by using low-adherence culture systems and iii) determined whether pharmacologically inhibiting ALDH increased their radiosensitivity. We found that chordoma samples have a unique transcriptomic signature characterized by a strong expression of hypoxia and glycolysis signaling pathways. Moreover, 3D cellular models of chordoma (derived from primary, relapse and metastatic tumors) reproduce histological and gene expression features of the disease. The metastatic, relapse and primary spheroids displayed high, medium and low radioresistance, respectively. Finally, inhibiting ALDH decreased the radioresistance in all three models. ; Les chordomes sont de rares tumeurs du squelette axial à croissance lente qui sont très agressives localement et ont un potentiel métastatique modéré. Ces tumeurs sont résistantes aux thérapies conventionnelles et restent à ce jour sans traitement spécifique. La prise en charge des patients consiste en une résection chirurgicale de la tumeur avec pour objectif d'obtenir des marges saines, accompagnée de radiothérapie à hautes doses. Malgré cette première ligne de traitement agressive, les récidives locales sont fréquentes et les options de traitement de seconde ligne sont limitées. Les mécanismes de ...