Project description DEENESFRITPL Understanding the origin and progression of rhabdoid tumours Malignant rhabdoid tumour is a highly aggressive, paediatric soft-tissue cancer with a low survival rate. It presents in various tissues including brain and kidney, and probably originates from aberrant differentiation during development. Understanding the origin and relationships of rhabdoid tumours is crucial for discovering new treatment options. The EU-funded RhabdoEvo project aims to identify the cellular origin of rhabdoid tumours and the molecular mechanisms driving disease progression and chemotherapy resistance. Having developed rhabdoid tumour organoid culture from patient tissue, researchers will apply single-cell epigenomic and transcriptomic analyses for characterisation of cellular identity and heterogeneity within tumours. Using genetic lineage-tracing technology to process the data obtained will help to uncover clonal dynamics in rhabdoid tumour progression and therapy resistance. Show the project objective Hide the project objective Objective 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. Fields of science medical and health sciencesclinical medicineoncologycolorectal cancernatural sciencesbiological sciencesgeneticsmutationnatural sciencesbiological sciencesgeneticsepigenetics Keywords Intratumor heterogeneity epigenetics tumor origin progression & therapy resistance lineage tracing Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2019-STG - ERC Starting Grant Call for proposal ERC-2019-STG See other projects for this call Funding Scheme ERC-STG - Starting Grant Host institution PRINSES MAXIMA CENTRUM VOOR KINDERONCOLOGIE BV Net EU contribution € 1 500 000,00 Address HEIDELBERGLAAN 25 3584CS Utrecht Netherlands See on map Region West-Nederland Utrecht Utrecht Activity type Other Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 500 000,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all PRINSES MAXIMA CENTRUM VOOR KINDERONCOLOGIE BV Netherlands Net EU contribution € 1 500 000,00 Address HEIDELBERGLAAN 25 3584CS Utrecht See on map Region West-Nederland Utrecht Utrecht Activity type Other Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 500 000,00
