Descrizione del progetto
Comprendere l’origine e la progressione dei tumori rabdoidi
Il tumore rabdoide maligno è un tumore pediatrico altamente aggressivo dei tessuti molli con un basso tasso di sopravvivenza. Si presenta in vari tessuti, tra cui cervello e reni, e probabilmente ha origine da una differenziazione aberrante durante lo sviluppo. Comprendere l’origine e i rapporti dei tumori rabdoidi è fondamentale per scoprire nuove opzioni di trattamento. Il progetto RhabdoEvo, finanziato dall’UE, si propone di identificare l’origine cellulare dei tumori rabdoidi e i meccanismi molecolari che guidano la progressione della malattia e la resistenza alla chemioterapia. Dopo aver sviluppato una cultura organoide del tumore rabdoide a partire dal tessuto del paziente, i ricercatori applicheranno analisi epigenomiche e trascrittomiche monocellulari per la caratterizzazione dell’identità cellulare e dell’eterogeneità all’interno dei tumori. L’utilizzo della tecnologia di tracciamento del lignaggio genetico per elaborare i dati ottenuti aiuterà a scoprire le dinamiche clonali nella progressione del tumore rabdoide e nella resistenza alla terapia.
Obiettivo
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.
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Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
3584CS Utrecht
Paesi Bassi