Deciphering the cellular origin and evolution of malignant rhabdoid tumors
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.