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| Status |
Public on Jun 13, 2024 |
| Title |
Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma [Methylation array] |
| Organism |
Mus musculus |
| Experiment type |
Methylation profiling by genome tiling array
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| Summary |
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 SMB21 and 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.
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| Overall design |
Murine cell line models of Sonic hedgehog medulloblastoma (SMB21 and SMB55) were treated with 3µM 5-azacytidine for 24 hours or corresponding concentration of DMOS solvent.
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| Contributor(s) |
Merk DJ |
| Citation missing |
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| |
| Submission date |
Jun 06, 2024 |
| Last update date |
Jun 13, 2024 |
| Contact name |
Daniel J. Merk |
| E-mail(s) |
daniel.merk@uni-tuebingen.de
|
| Organization name |
Hertie-Institute for Clinical Brain Research
|
| Street address |
Otfried-Müller-Str. 27
|
| City |
Tübingen |
| ZIP/Postal code |
72076 |
| Country |
Germany |
| |
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| Platforms (1) |
| GPL30650 |
Infinium Mouse Methylation BeadChip |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE269463 |
Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma |
|
| Relations |
| BioProject |
PRJNA1120852 |
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