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Developing neural crest organoids with inducible neuroblastoma to model chemoresistance in MYCN amplification related high-risk cases

Descrizione del progetto

Modellizzazione della farmacoresistenza nel neuroblastoma

Il neuroblastoma, che costituisce il terzo tipo di tumore più diffuso nei bambini, ha origine nel sistema nervoso simpatico da cellule progenitrici della cresta neurale. Nel 20 % dei casi tale carcinoma si associa a una prognosi sfavorevole e a un’amplificazione dell’oncogene MYCN. Ciononostante, i meccanismi di resistenza al trattamento sono tuttora poco compresi. Per compiere progressi in questo ambito, il progetto NeuroblastORG, finanziato dall’UE, propone di sviluppare un modello di organoide umano per le cellule della cresta neurale a partire da cellule staminali pluripotenti indotte. L’idea è quella di ricapitolare le specifiche fasi dello sviluppo embrionale nella linea cellulare della cresta neurale e di modellare il neuroblastoma attraverso una sovraespressione dell’oncogene MYCN. In tal modo i ricercatori avranno la possibilità di analizzare l’efficacia di vari farmaci e di approfondire i meccanismi alla base della chemioresistenza nel neuroblastoma.

Obiettivo

Neuroblastoma (NB) is the most common cancer in infants and the 3rd most common cancer in children. According to the WHO 90% of NBs occur in children younger than 5 years old and 15% of all pediatric cancer related death are due to NB. Approximately 20% of NB cases are characterized by the amplification of the MYCN gene, which is linked to more aggressive tumors and poor prognosis (high-risk NB). Despite recent treatment advances, relapsing high-risk NB often leads to death. Understanding mechanisms of therapy resistance can help to develop more effective treatment protocols. However, investigation of acquired resistance upon chemotherapy is largely limited by the number of patients with high-risk NB and the availability of adequate model systems. Mice models of NB are often used, however species specific differences in sympathoblast development might result in misleading findings. Sympathoblast are the fetal counterparts of NB cancer cells and they are derived from the neural crest (NC).
The overall aim of the NeuroblastORG project is to establish a human organoid model of the NC lineage, which can recapitulate human specific embryonic developmental stages, while also giving rise to sympathoblast-like NB cells, in addition to healthy sympathoadrenergic lineage derivatives (NB organoid). To reach this aim, human induced pluripotent stem cell lines will be genetically modified to overexpress the MYCN gene under the control of an NC-specific promoter, but only in a subset of NC cells within the organoids. Relevance of the established model will be validated by comparing gene expression signatures between NB organoids and human NB patient tumour samples.
The NB organoid model system will provide a platform to simulate treatment of NB cells with NB-therapy relevant agents and monitor the effect of the applied treatment, allowing the investigation of human NB-specific chemoresistance acquisition in MYCN amplification related high-risk cases.

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Coordinatore

HUN-REN TERMESZETTUDOMANYI KUTATOKOZPONT
Contribution nette de l'UE
€ 157 622,40
Indirizzo
Magyar tudosok korutja 2
1117 Budapest
Ungheria

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Regione
Közép-Magyarország Budapest Budapest
Tipo di attività
Other
Collegamenti
Contributo UE
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