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

Abstract

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.

Phosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma

“…Activation of Shh signaling increased phosphorylation of p38, and inhibition of p38 significantly attenuated Shh-dependent upregulation of Gli1 in astrocytes 39 , whereas phospho-p38 levels in the joint tissue of collagen-induced arthritis was decreased after blockade of SHH signaling 40 . However, a previous study on children MB SHH -derived xenografts indicated p38 kinase MAP2K3/MKK3 and the p38 effector MAPKAPK2/MK2 were significantly upregulated, as compared to Group 3 or 4 MB xenografts 41 , and a previous study demonstrated the level of p38α increased significantly during the proliferation of cerebellar granule cell precursors, and inhibition of SHH signaling or granule cell precursor proliferation decreased p38α levels 42 . These findings appear to be at odds with our study that p38 is inactivated in children and mouse MB SHH .…”