4.7 Article

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

期刊

JOURNAL OF PROTEOME RESEARCH
卷 -, 期 -, 页码 -

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jproteome.2c00203

关键词

medulloblastoma; pediatric; brain tumor; proteomics; kinase activity; patient-derived xenograft (PDX); actinomycin D; MYC

资金

  1. Fondatioun Kriibskrank Kanner
  2. National Cancer Institute [U24 CA220341, U24 CA248457, U01 CA184898, 2R01 CA159859, P30 CA30199]
  3. National Institute for Neurological Disorders and Stroke [R01 NS096368]
  4. National Cancer Institute of the National Institutes of Health [P30CA033572]
  5. Ben and Catherine Ivy Foundation

向作者/读者索取更多资源

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, classified into different molecular subgroups. Mass spectrometry-based proteomics and phosphoproteomics were used to study MB, and the PDX tumors of MB were found to have similar proteomic profiles with primary human MB tumors. Additionally, several potential pathways that could serve as new therapeutic targets for MB were identified.
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 NF kappa B 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.

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