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

Descripción del proyecto

Modelización de la farmacorresistencia de los neuroblastomas

El neuroblastoma, el tercer tumor maligno más frecuente en niños, se origina en el sistema nervioso simpático a partir de células progenitoras de la cresta neural. En el 20 % de los casos, el neuroblastoma tiene mal pronóstico y está relacionado con la amplificación del oncogén MYCN. Sin embargo, todavía no se conocen bien los mecanismos de resistencia al tratamiento. Para avanzar al respecto, el equipo del proyecto NeuroblastORG, financiado con fondos europeos, propone desarrollar un modelo organoide humano de células de la cresta neural a partir de células madre pluripotentes inducidas. La idea es recapitular las etapas específicas del desarrollo embrionario del linaje de la cresta neural y modelizar el neuroblastoma mediante la sobreexpresión del oncogén MYCN. Esto permitirá a los investigadores comprobar la eficacia de diversos fármacos y estudiar el mecanismo de quimiorresistencia del neuroblastoma.

Objetivo

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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Coordinador

HUN-REN TERMESZETTUDOMANYI KUTATOKOZPONT
Aportación neta de la UEn
€ 157 622,40
Dirección
Magyar tudosok korutja 2
1117 Budapest
Hungría

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Región
Közép-Magyarország Budapest Budapest
Tipo de actividad
Other
Enlaces
Aportación de la UE
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