MYC Promotes Aggressive Growth and Metastasis of a WNT-Medulloblastoma Mouse Model

Abstract Medulloblastoma (MB), the most common malignant pediatric brain tumor, comprises four molecularly and clinically distinct subgroups (termed WNT, SHH, group 3, and group 4). Prognosis varies based on genetic and pathological features associated with each molecular subgroup. WNT-MB, considere...

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Bibliographic Details
Published inDevelopmental neuroscience Vol. 46; no. 3; pp. 167 - 178
Main Authors Hartley, Rachel, Phoenix, Timothy N.
Format Journal Article
LanguageEnglish
Published Basel, Switzerland 01.05.2024
Subjects
Animals
Cerebellar Neoplasms - genetics
Cerebellar Neoplasms - pathology
Developmental Neurobiology of Brain Tumors: Mini-Review
Disease Models, Animal
Medulloblastoma - genetics
Medulloblastoma - metabolism
Medulloblastoma - pathology
Mice
Neoplasm Metastasis - genetics
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Wnt Proteins - genetics
Wnt Proteins - metabolism
Metastasis
Immune evasion
Medulloblastoma
Myc
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Summary:Abstract Medulloblastoma (MB), the most common malignant pediatric brain tumor, comprises four molecularly and clinically distinct subgroups (termed WNT, SHH, group 3, and group 4). Prognosis varies based on genetic and pathological features associated with each molecular subgroup. WNT-MB, considered low-risk, is rarely metastatic and contains activating mutations in CTNNB1; group 3-MB (GRP3-MB), commonly classified as high-risk, is frequently metastatic and can contain genomic alterations, resulting in elevated MYC expression. Here, we compare model systems of low-risk WNT-MB and high-risk GRP3-MB to identify tumor and microenvironment interactions that could contribute to features associated with prognosis. Compared to GRP3-MB, we find that WNT-MB is enriched in gene sets related to extracellular matrix (ECM) regulation and cellular adhesion. Exogenous expression of MycT58A in a murine WNT-MB model significantly accelerates growth and results in metastatic disease. In addition to decreased ECM regulation and cell adhesion pathways, we also identified immune system interactions among the top downregulated signaling pathways following MycT58A expression. Taken together, our data provide evidence that increased Myc signaling can promote the growth and metastasis in a murine model of WNT-MB.
ISSN:0378-5866
1421-9859
DOI:10.1159/000533270