Journal Article

DKFZ-2024-01607

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma.

Tsiami, F. ; Lago, C. ; Pozza, N. ; Piccioni, F. ; Zhao, X. ; Lülsberg, F. ; Root, D. E. ; Tiberi, L. ; Kool, M.DKFZ* ; Schittenhelm, J. ; Bandopadhayay, P. ; Segal, R. A. ; Tabatabai, G.DKFZ* ; Merk, D. J.

2024
Biomed Central London

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Please use a persistent id in citations: doi:10.1186/s40478-024-01831-x

Abstract: 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.

Keyword(s): Medulloblastoma: genetics (MeSH) ; Medulloblastoma: metabolism (MeSH) ; Medulloblastoma: pathology (MeSH) ; Animals (MeSH) ; DNA (Cytosine-5-)-Methyltransferase 1: genetics (MeSH) ; DNA (Cytosine-5-)-Methyltransferase 1: metabolism (MeSH) ; Hedgehog Proteins: metabolism (MeSH) ; Hedgehog Proteins: genetics (MeSH) ; CRISPR-Cas Systems (MeSH) ; Cerebellar Neoplasms: genetics (MeSH) ; Cerebellar Neoplasms: metabolism (MeSH) ; Cerebellar Neoplasms: pathology (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Cell Line, Tumor (MeSH) ; Smoothened Receptor: genetics (MeSH) ; Smoothened Receptor: metabolism (MeSH) ; Gene Knockout Techniques: methods (MeSH) ; Combinatorial treatment ; DNMT1 ; Functional genomics ; Medulloblastoma ; SHH pathway ; Synergy ; DNA (Cytosine-5-)-Methyltransferase 1 ; Hedgehog Proteins ; DNMT1 protein, human ; Dnmt1 protein, mouse ; Smoothened Receptor

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)
3. DKTK Koordinierungsstelle Tübingen (TU01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

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