Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma.

Autor: Tsiami F; Department of Neurology and Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University, Tübingen, Germany., Lago C; Armenise-Harvard Laboratory of Brain Disorders and Cancer, CIBIO, Trento, Italy., Pozza N; Armenise-Harvard Laboratory of Brain Disorders and Cancer, CIBIO, Trento, Italy., Piccioni F; Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Merck Research Laboratories, Cambridge, MA, USA., Zhao X; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Lülsberg F; Institute for Anatomy, Anatomy and Cell Biology, Rheinische Friedrich-Wilhelms-University, Bonn, Germany., Root DE; Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Tiberi L; Armenise-Harvard Laboratory of Brain Disorders and Cancer, CIBIO, Trento, Italy., Kool M; Hopp Children's Cancer Center (KITZ), Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Research Consortium (DKTK), Heidelberg, Germany.; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.; University Medical Center Utrecht, Utrecht, the Netherlands., Schittenhelm J; Department of Pathology and Neuropathology, Institute of Neuropathology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.; Comprehensive Cancer Center Tübingen Stuttgart, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany., Bandopadhayay P; Dana-Farber/Boston Children´S Cancer and Blood Disorders Center, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, USA., Segal RA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Tabatabai G; Department of Neurology and Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.; Comprehensive Cancer Center Tübingen Stuttgart, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University, Tübingen, Germany.; German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Partner Site Tübingen, Heidelberg, Germany., Merk DJ; Department of Neurology and Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany. daniel.merk@uni-tuebingen.de.; Cluster of Excellence iFIT (EXC 2180) 'Image Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University, Tübingen, Germany. daniel.merk@uni-tuebingen.de.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2024 Aug 07; Vol. 12 (1), pp. 125. Date of Electronic Publication: 2024 Aug 07.
DOI: 10.1186/s40478-024-01831-x
Abstrakt: Sonic hedgehog subgroup of medulloblastoma (SHH-MB) is characterized by aberrant activation of the SHH signaling pathway. An inhibition of the positive SHH regulator Smoothened (SMO) has demonstrated promising clinical efficacy. Yet, primary and acquired resistance to SMO inhibitors limit their efficacy. An understanding of underlying molecular mechanisms of resistance to therapy is warranted to bridge this unmet need. Here, we make use of genome-wide CRISPR-Cas9 knockout screens in murine SMB21 and human DAOY cells, in order to unravel genetic dependencies and drug-related genetic interactors that could serve as alternative therapeutic targets for SHH-MB. Our screens reinforce SMB21 cells as a faithful model system for SHH-MB, as opposed to DAOY cells, and identify members of the epigenetic machinery including DNA methyltransferase 1 (DNMT1) as druggable targets in SHH-dependent tumors. We show that Dnmt1 plays a crucial role in normal murine cerebellar development and is required for SHH-MB growth in vivo. Additionally, DNMT1 pharmacological inhibition alone and in combination with SMO inhibition effectively inhibits tumor growth in murine and human SHH-MB cell models and prolongs survival of SHH-MB mouse models by inhibiting SHH signaling output downstream of SMO. In conclusion, our data highlight the potential of inhibiting epigenetic regulators as a novel therapeutic avenue in SMO-inhibitor sensitive as well as resistant SHH-MBs.
(© 2024. The Author(s).)
Databáze: MEDLINE
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