Descripción del proyecto
Comprender el origen y la progresión de los tumores rabdoides
Un tumor rabdoide maligno es un tipo de cáncer de los tejidos blandos de los niños, muy agresivo y que tiene una tasa de supervivencia muy baja. Se presenta en diversos tejidos, incluido el cerebro y los riñones, y es probable que se origine a partir de una diferenciación anormal durante el desarrollo. Comprender el origen y las relaciones de los tumores rabdoides es crucial para descubrir nuevas opciones terapéuticas. El proyecto financiado con fondos europeos RhabdoEvo busca identificar el origen celular de los tumores rabdoides y los mecanismos moleculares que impulsan la progresión de la enfermedad y la resistencia a la quimioterapia. Una vez que hayan desarrollado un cultivo organoide de tumor rabdoide a partir de tejido del paciente, los investigadores aplicarán análisis unicelulares transcriptómicos y epigenómicos para caracterizar la identidad celular y la heterogeneidad de los tumores. El uso de la tecnología de trazado del linaje genético para procesar los datos obtenidos ayudará a descubrir dinámicas clonales de la progresión del tumor rabdoide y la resistencia al tratamiento.
Objetivo
Introduction How tumors adapt to changing environmental conditions and treatment is a major unsolved problem frustrating effective therapy. Rhabdoid tumors are highly aggressive pediatric tumors with a low survival rate. They occur in multiple tissues, including brain and kidney, and likely originate as a consequence of aberrant differentiation during development. Understanding the origin of rhabdoid tumors and the relationship with normal development is crucial for investigating new treatment options. The almost certain appearance of therapy resistance, low mutation burden, and recent epigenetic profiling suggest the existence of epigenetic heterogeneity within rhabdoid tumors. We hypothesize that epigenetic heterogeneity within rhabdoid tumors underlies their aggressive behavior. Goal I previously exploited organoid models and CRISPR technology to study colorectal cancer progression. My lab now developed a protocol to, for the first time, efficiently grow rhabdoid tumor organoids from patient tissue. We are in the unique position to identify the cellular origin of rhabdoid tumors and the key molecular mechanisms driving disease progression and therapy resistance. Approach We will I) apply single-cell epigenomic and transcriptomic analyses on tumor tissue for in-depth characterization of the cellular identity and heterogeneity within rhabdoid tumors II) combine our unique rhabdoid tumor organoids with genetic lineage tracing technology to reveal clonal dynamics in rhabdoid tumor progression and therapy resistance III) perform retrospective lineage tracing using somatic mutations to track down the cell-of-origin of rhabdoid tumors. Innovation Our integrative use of state-of-the-art technologies on unique patient-derived tissue and tumor organoids will provide comprehensive insights into the origin, heterogeneity and progression of rhabdoid tumors. This will also establish novel approaches for other cancer research as well as new concepts for improving therapy.
Ámbito científico
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Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
3584CS Utrecht
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