Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors
Abstract Background Atypical teratoid rhabdoid tumors (ATRT) are incurable high-grade pediatric brain tumors. Despite intensive research efforts, the prognosis for ATRT patients under currently established treatment protocols is poor. While novel therapeutic strategies are urgently needed, the gener...
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2024-12-01
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| author | Daniel J. Merk Foteini Tsiami Sophie Hirsch Bianca Walter Lara A. Haeusser Jens D. Maile Aaron Stahl Mohamed A. Jarboui Anna Lechado-Terradas Franziska Klose Sepideh Babaei Jakob Admard Nicolas Casadei Cristiana Roggia Michael Spohn Jens Schittenhelm Stephan Singer Ulrich Schüller Federica Piccioni Nicole S. Persky Manfred Claassen Marcos Tatagiba Philipp J. Kahle David E. Root Markus Templin Ghazaleh Tabatabai |
| author_facet | Daniel J. Merk Foteini Tsiami Sophie Hirsch Bianca Walter Lara A. Haeusser Jens D. Maile Aaron Stahl Mohamed A. Jarboui Anna Lechado-Terradas Franziska Klose Sepideh Babaei Jakob Admard Nicolas Casadei Cristiana Roggia Michael Spohn Jens Schittenhelm Stephan Singer Ulrich Schüller Federica Piccioni Nicole S. Persky Manfred Claassen Marcos Tatagiba Philipp J. Kahle David E. Root Markus Templin Ghazaleh Tabatabai |
| author_sort | Daniel J. Merk |
| collection | DOAJ |
| description | Abstract Background Atypical teratoid rhabdoid tumors (ATRT) are incurable high-grade pediatric brain tumors. Despite intensive research efforts, the prognosis for ATRT patients under currently established treatment protocols is poor. While novel therapeutic strategies are urgently needed, the generation of molecular-driven treatment concepts is a challenge mainly due to the absence of actionable genetic alterations. Results We here use a functional genomics approach to identify genetic dependencies in ATRT, validate selected hits using a functionally instructed small molecule drug library, and observe preferential activity in ATRT cells without subgroup-specific selectivity. CDK4/6 inhibitors are among the most potent drugs and display anti-tumor efficacy due to mutual exclusive dependency on CDK4 or CDK6. Chemogenetic interactor screens reveal a broad spectrum of G1 phase cell cycle regulators that differentially enable cell cycle progression and modulate response to CDK4/6 inhibition in ATRT cells. In this regard, we find that the ubiquitin ligase substrate receptor AMBRA1 acts as a context-specific inhibitor of cell cycle progression by regulating key components of mitosis including aurora kinases. Conclusions Our data provide a comprehensive resource of genetic and chemical dependencies in ATRTs, which will inform further preclinical evaluation of novel targeted therapies for this tumor entity. Furthermore, this study reveals a unique mechanism of cell cycle inhibition as the basis for tumor suppressive functions of AMBRA1. |
| format | Article |
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| institution | OA Journals |
| issn | 1474-760X |
| language | English |
| publishDate | 2024-12-01 |
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| series | Genome Biology |
| spelling | doaj-art-c3f097f8f86b4c4a8b8f3ec94c994ed52025-08-20T02:20:38ZengBMCGenome Biology1474-760X2024-12-0125113810.1186/s13059-024-03438-wFunctional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumorsDaniel J. Merk0Foteini Tsiami1Sophie Hirsch2Bianca Walter3Lara A. Haeusser4Jens D. Maile5Aaron Stahl6Mohamed A. Jarboui7Anna Lechado-Terradas8Franziska Klose9Sepideh Babaei10Jakob Admard11Nicolas Casadei12Cristiana Roggia13Michael Spohn14Jens Schittenhelm15Stephan Singer16Ulrich Schüller17Federica Piccioni18Nicole S. Persky19Manfred Claassen20Marcos Tatagiba21Philipp J. Kahle22David E. Root23Markus Templin24Ghazaleh Tabatabai25Department of Neurology and Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Eberhard Karls University TübingenDepartment of Neurology and Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Eberhard Karls University TübingenDepartment of Neurology and Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Eberhard Karls University TübingenDepartment of Neurology and Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Eberhard Karls University TübingenDepartment of Neurology and Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Eberhard Karls University TübingenDepartment of Neurology and Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Eberhard Karls University TübingenNMI Natural and Medical Sciences Institute at the University of TübingenInstitute for Ophtalmic Research, Department for Ophtalmology, University Hospital Tübingen, Eberhard Karls University TübingenLaboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative DiseasesInstitute for Ophtalmic Research, Department for Ophtalmology, University Hospital Tübingen, Eberhard Karls University TübingenInternal Medicine I, University Hospital Tübingen, Eberhard Karls University TübingenInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Eberhard Karls University TübingenInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Eberhard Karls University TübingenInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Eberhard Karls University TübingenResearch Institute Children’s Cancer CenterInstitute of Neuropathology, Department of Pathology and Neuropathology, University Hospital Tübingen, Eberhard Karls University TübingenInstitute of General and Molecular Pathology, Department of Pathology and Neuropathology, University Hospital Tübingen, Eberhard Karls University TübingenResearch Institute Children’s Cancer CenterGenetic Perturbation Platform, Broad Institute of MIT and HarvardGenetic Perturbation Platform, Broad Institute of MIT and HarvardInternal Medicine I, University Hospital Tübingen, Eberhard Karls University TübingenDepartment of Neurosurgery, University Hospital Tübingen, Eberhard Karls University TübingenLaboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative DiseasesGenetic Perturbation Platform, Broad Institute of MIT and HarvardNMI Natural and Medical Sciences Institute at the University of TübingenDepartment of Neurology and Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Eberhard Karls University TübingenAbstract Background Atypical teratoid rhabdoid tumors (ATRT) are incurable high-grade pediatric brain tumors. Despite intensive research efforts, the prognosis for ATRT patients under currently established treatment protocols is poor. While novel therapeutic strategies are urgently needed, the generation of molecular-driven treatment concepts is a challenge mainly due to the absence of actionable genetic alterations. Results We here use a functional genomics approach to identify genetic dependencies in ATRT, validate selected hits using a functionally instructed small molecule drug library, and observe preferential activity in ATRT cells without subgroup-specific selectivity. CDK4/6 inhibitors are among the most potent drugs and display anti-tumor efficacy due to mutual exclusive dependency on CDK4 or CDK6. Chemogenetic interactor screens reveal a broad spectrum of G1 phase cell cycle regulators that differentially enable cell cycle progression and modulate response to CDK4/6 inhibition in ATRT cells. In this regard, we find that the ubiquitin ligase substrate receptor AMBRA1 acts as a context-specific inhibitor of cell cycle progression by regulating key components of mitosis including aurora kinases. Conclusions Our data provide a comprehensive resource of genetic and chemical dependencies in ATRTs, which will inform further preclinical evaluation of novel targeted therapies for this tumor entity. Furthermore, this study reveals a unique mechanism of cell cycle inhibition as the basis for tumor suppressive functions of AMBRA1.https://doi.org/10.1186/s13059-024-03438-wFunctional screeningCRISPR-Cas9Genetic dependenciesRhabdoid tumorsCDK4/6 inhibitorsAMBRA1 |
| spellingShingle | Daniel J. Merk Foteini Tsiami Sophie Hirsch Bianca Walter Lara A. Haeusser Jens D. Maile Aaron Stahl Mohamed A. Jarboui Anna Lechado-Terradas Franziska Klose Sepideh Babaei Jakob Admard Nicolas Casadei Cristiana Roggia Michael Spohn Jens Schittenhelm Stephan Singer Ulrich Schüller Federica Piccioni Nicole S. Persky Manfred Claassen Marcos Tatagiba Philipp J. Kahle David E. Root Markus Templin Ghazaleh Tabatabai Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors Genome Biology Functional screening CRISPR-Cas9 Genetic dependencies Rhabdoid tumors CDK4/6 inhibitors AMBRA1 |
| title | Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors |
| title_full | Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors |
| title_fullStr | Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors |
| title_full_unstemmed | Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors |
| title_short | Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors |
| title_sort | functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors |
| topic | Functional screening CRISPR-Cas9 Genetic dependencies Rhabdoid tumors CDK4/6 inhibitors AMBRA1 |
| url | https://doi.org/10.1186/s13059-024-03438-w |
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