Subgroup-Enriched Pathways and Kinase Signatures in Medulloblastoma Patient-Derived Xenografts

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is classified into four primary molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), and further genomic and proteomic subtypes have been reported. Subgroup heterogeneity and few actiona...

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Published in:Journal of proteome research 2022-09, Vol.21 (9), p.2124-2136
Main Authors: Leskoske, Kristin L., Garcia-Mansfield, Krystine, Sharma, Ritin, Krishnan, Aparna, Rusert, Jessica M., Mesirov, Jill P., Wechsler-Reya, Robert J., Pirrotte, Patrick
Format: Article
Language:English
Subjects:
Animals
Brain Neoplasms - genetics
Cerebellar Neoplasms - genetics
Cerebellar Neoplasms - metabolism
Cerebellar Neoplasms - pathology
Child
Disease Models, Animal
Hedgehog Proteins - genetics
Hedgehog Proteins - metabolism
Hedgehog Proteins - therapeutic use
Heterografts
Humans
Medulloblastoma - genetics
Medulloblastoma - metabolism
Medulloblastoma - pathology
Proteomics
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Summary:Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is classified into four primary molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), and further genomic and proteomic subtypes have been reported. Subgroup heterogeneity and few actionable mutations have hindered the development of targeted therapies, especially for G3 MB, which has a particularly poor prognosis. To identify novel therapeutic targets for MB, we performed mass spectrometry-based deep expression proteomics and phosphoproteomics in 20 orthotopic patient-derived xenograft (PDX) models of MB comprising SHH, G3, and G4 subgroups. We found that the proteomic profiles of MB PDX tumors are closely aligned with those of primary human MB tumors illustrating the utility of PDX models. SHH PDXs were enriched for NFκB and p38 MAPK signaling, while G3 PDXs were characterized by MYC activity. Additionally, we found a significant association between actinomycin D sensitivity and increased abundance of MYC and MYC target genes. Our results highlight several candidate pathways that may serve as targets for new MB therapies. Mass spectrometry data are available via ProteomeXchange with identifier PXD035070.
ISSN:1535-3893
1535-3907
DOI:10.1021/acs.jproteome.2c00203