TY  - JOUR
AU  - Tsiami, Foteini
AU  - Lago, Chiara
AU  - Pozza, Noemi
AU  - Piccioni, Federica
AU  - Zhao, Xuesong
AU  - Lülsberg, Fabienne
AU  - Root, David E
AU  - Tiberi, Luca
AU  - Kool, Marcel
AU  - Schittenhelm, Jens
AU  - Bandopadhayay, Pratiti
AU  - Segal, Rosalind A
AU  - Tabatabai, Ghazaleh
AU  - Merk, Daniel J
TI  - Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma.
JO  - Acta Neuropathologica Communications
VL  - 12
IS  - 1
SN  - 2051-5960
CY  - London
PB  - Biomed Central
M1  - DKFZ-2024-01607
SP  - 125
PY  - 2024
AB  - 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.
KW  - Medulloblastoma: genetics
KW  - Medulloblastoma: metabolism
KW  - Medulloblastoma: pathology
KW  - Animals
KW  - DNA (Cytosine-5-)-Methyltransferase 1: genetics
KW  - DNA (Cytosine-5-)-Methyltransferase 1: metabolism
KW  - Hedgehog Proteins: metabolism
KW  - Hedgehog Proteins: genetics
KW  - CRISPR-Cas Systems
KW  - Cerebellar Neoplasms: genetics
KW  - Cerebellar Neoplasms: metabolism
KW  - Cerebellar Neoplasms: pathology
KW  - Humans
KW  - Mice
KW  - Cell Line, Tumor
KW  - Smoothened Receptor: genetics
KW  - Smoothened Receptor: metabolism
KW  - Gene Knockout Techniques: methods
KW  - Combinatorial treatment (Other)
KW  - DNMT1 (Other)
KW  - Functional genomics (Other)
KW  - Medulloblastoma (Other)
KW  - SHH pathway (Other)
KW  - Synergy (Other)
KW  - DNA (Cytosine-5-)-Methyltransferase 1 (NLM Chemicals)
KW  - Hedgehog Proteins (NLM Chemicals)
KW  - DNMT1 protein, human (NLM Chemicals)
KW  - Dnmt1 protein, mouse (NLM Chemicals)
KW  - Smoothened Receptor (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39107797
DO  - DOI:10.1186/s40478-024-01831-x
UR  - https://inrepo02.dkfz.de/record/292108
ER  -