MYC overexpression and SMARCA4 loss cooperate to drive medulloblastoma formation in mice

TY - JOUR

T1 - MYC overexpression and SMARCA4 loss cooperate to drive medulloblastoma formation in mice

AU - Göbel, Carolin

AU - Godbole, Shweta

AU - Schoof, Melanie

AU - Holdhof, Dörthe

AU - Kresbach, Catena

AU - Loose, Carolin

AU - Neumann, Julia

AU - Schüller, Ulrich

N1 - © 2023. The Author(s).

PY - 2023/11/2

Y1 - 2023/11/2

N2 - Group 3 medulloblastoma is one of the most aggressive types of childhood brain tumors. Roughly 30% of cases carry genetic alterations in MYC, SMARCA4, or both genes combined. While overexpression of MYC has previously been shown to drive medulloblastoma formation in mice, the functional significance of SMARCA4 mutations and their suitability as a therapeutic target remain largely unclear. To address this issue, we combined overexpression of MYC with a loss of SMARCA4 in granule cell precursors. Both alterations did not increase proliferation of granule cell precursors in vitro. However, combined MYC overexpression and SMARCA4 loss successfully induced tumor formation in vivo after orthotopic transplantation in recipient mice. Resulting tumors displayed anaplastic histology and exclusively consisted of SMARCA4-negative cells although a mixture of recombined and non-recombined cells was injected. These observations provide first evidence for a tumor-promoting role of a SMARCA4 deficiency in the development of medulloblastoma. In comparing the transcriptome of tumors to the cells of origin and an established Sonic Hedgehog medulloblastoma model, we gathered first hints on deregulated gene expression that could be specifically involved in SMARCA4/MYC driven tumorigenesis. Finally, an integration of RNA sequencing and DNA methylation data of murine tumors with human samples revealed a high resemblance to human Group 3 medulloblastoma on the molecular level. Altogether, the development of SMARCA4-deficient medulloblastomas in mice paves the way to deciphering the role of frequently occurring SMARCA4 alterations in Group 3 medulloblastoma with the perspective to explore targeted therapeutic options.

AB - Group 3 medulloblastoma is one of the most aggressive types of childhood brain tumors. Roughly 30% of cases carry genetic alterations in MYC, SMARCA4, or both genes combined. While overexpression of MYC has previously been shown to drive medulloblastoma formation in mice, the functional significance of SMARCA4 mutations and their suitability as a therapeutic target remain largely unclear. To address this issue, we combined overexpression of MYC with a loss of SMARCA4 in granule cell precursors. Both alterations did not increase proliferation of granule cell precursors in vitro. However, combined MYC overexpression and SMARCA4 loss successfully induced tumor formation in vivo after orthotopic transplantation in recipient mice. Resulting tumors displayed anaplastic histology and exclusively consisted of SMARCA4-negative cells although a mixture of recombined and non-recombined cells was injected. These observations provide first evidence for a tumor-promoting role of a SMARCA4 deficiency in the development of medulloblastoma. In comparing the transcriptome of tumors to the cells of origin and an established Sonic Hedgehog medulloblastoma model, we gathered first hints on deregulated gene expression that could be specifically involved in SMARCA4/MYC driven tumorigenesis. Finally, an integration of RNA sequencing and DNA methylation data of murine tumors with human samples revealed a high resemblance to human Group 3 medulloblastoma on the molecular level. Altogether, the development of SMARCA4-deficient medulloblastomas in mice paves the way to deciphering the role of frequently occurring SMARCA4 alterations in Group 3 medulloblastoma with the perspective to explore targeted therapeutic options.

KW - Animals

KW - Humans

KW - Mice

KW - Brain Neoplasms/genetics

KW - Cerebellar Neoplasms/metabolism

KW - DNA Helicases/genetics

KW - Hedgehog Proteins/metabolism

KW - Medulloblastoma/metabolism

KW - Nuclear Proteins/genetics

KW - Transcription Factors/genetics

KW - Transcriptome

U2 - 10.1186/s40478-023-01654-2

DO - 10.1186/s40478-023-01654-2

M3 - SCORING: Journal article

C2 - 37919824

VL - 11

SP - 174

JO - ACTA NEUROPATHOL COM

JF - ACTA NEUROPATHOL COM

SN - 2051-5960

IS - 1

ER -