| Autor: |
Leskoske KL; Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, United States., Garcia-Mansfield K; Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, United States.; Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States., Sharma R; Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, United States.; Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States., Krishnan A; Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, United States., Rusert JM; Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States., Mesirov JP; Department of Medicine, University of California San Diego, La Jolla, California 92093, United States.; Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States., Wechsler-Reya RJ; Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States., Pirrotte P; Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, United States.; Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States. |
| Abstrakt: |
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. |
