Abstract
Medulloblastoma, a common malignant brain tumor in children, comprises four molecular subgroups WNT, SHH, Group 3, and Group 4. In the present study, we performed a deep proteome-based investigation of SHH, Group 3 and Group 4 tumors. The adult SHH medulloblastomas were found to have a distinct proteomic profile. Several RNA metabolism-related pathways including mRNA splicing, 5′ to 3′ RNA decay, 3′ to 5′ RNA decay by the RNA exosome, and the N6-methyladenosine modification of RNA were enriched in adult SHH tumors. The heightened expression of the RNA surveillance pathways is likely to be essential for the viability of adult SHH subgroup medulloblastomas, which carry mutations in U1snRNA encoding gene and thus could be a vulnerability of these tumors. Group 3 and Group 4 medulloblastomas, on the other hand, are known to have an overlap in their expression profiles and underlying genetic alterations. Group 3 proteome was found to be distinctively enriched in several metabolic pathways including glycolysis, gluconeogenesis, glutamine anabolism, glutathione-mediated anti-oxidant pathway, and drug metabolism pathway suggests that the extensive metabolic rewiring is likely to be responsible for the aggressive clinical behavior of Group 3 tumors. This comprehensive proteomic analysis has provided valuable insight into the biology of Group 3 and adult SHH medulloblastomas, which could be further explored for effective treatment of these tumors.
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Acknowledgements
We would like to acknowledge Uchhatar Avishkar Yojana (UAY-(MHRD), project #34_IITB (2016) to SS, and University Grants Commission fellowship to MKP. MASSFIITB (Mass Spectrometry Facility, IIT Bombay) supported by Department of Biotechnology (BT/PR13114/INF/22/206/2015) for MS-based proteomics work is gratefully acknowledged.
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MKP, NS, and SS designed the study. MKP performed the experiments. The data analysis was done by AK, MKP, and NS. DB performed the gene enrichment analysis and visualization. The surgery and pathology of the tumors were done by AM, PS, TG & ES.
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The current study was approved by the Institute Ethics Committee of Tata Memorial hospital (Project number 197) and Indian Institute of Technology Bombay (Project number 018).
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KP, M., Kumar, A., Biswas, D. et al. The proteomic analysis shows enrichment of RNA surveillance pathways in adult SHH and extensive metabolic reprogramming in Group 3 medulloblastomas. Brain Tumor Pathol 38, 96–108 (2021). https://doi.org/10.1007/s10014-020-00391-x
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DOI: https://doi.org/10.1007/s10014-020-00391-x