Developmental basis of SHH medulloblastoma heterogeneity

Maxwell P. Gold, Winnie Ong, Andrew M. Masteller, David R. Ghasemi, Julie Anne Galindo, Noel R. Park, Nhan C. Huynh, Aneesh Donde, Veronika Pister, Raul A. Saurez, Maria C. Vladoiu, Grace H. Hwang, Tanja Eisemann, Laura K. Donovan, Adam D. Walker, Joseph Benetatos, Christelle Dufour, Livia Garzia, Rosalind A. Segal, Robert J. Wechsler-Reya, Jill P. Mesirov, Andrey Korshunov, Kristian W. Pajtler, Scott L. Pomeroy, Olivier Ayrault, Shawn M. Davidson, Jennifer A. Cotter, Michael D. Taylor, Ernest Fraenkel. Nat Commun. 2024 Jan 8;15(1):270. doi: 10.1038/s41467-023-44300-0. PMID: 38191555; PMCID: PMC10774283.

ABSTRACT

Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different developmental stages. Additionally, using multiplexed proteomic imaging and MALDI imaging mass spectrometry, we identify distinct histological and metabolic profiles for highly differentiated tumors. Our approaches are applicable to understanding the interplay between heterogeneity and differentiation in other cancers and can provide important insights for the design of targeted therapies.

SUPPLEMENTAL MATERIAL

Paper: Gold et al. 2024
Supplementary Information
- Supplementary Information
- Description of Additional Supplementary Files
Supplemental Figures
Supplemental Data
Data Availability
- The raw scRNA-seq and snRNA-seq data generated for this manuscript have been deposited in GEO under the accession number GSE214469. The previously published data used for this work can be accessed through the following GEO accession numbers: scRNA-seq data from Riemondy et al. GSE156053, scRNA-seq data from Hovestadt et al. GSE119926, scRNA-seq data from Vladoiu et al. GSE118068, and bulk RNA transcriptomics from Cavalli et al. GSE85218.
- mIHC imaging data can be found at https://zenodo.org/records/10257144 and taurine-focused IHC imaging can be found at https://zenodo.org/records/10256482. Processed omics data can be found with the corresponding code at https://github.com/fraenkel-lab/shh-mben. The remaining data are available within the Article, Supplementary Information, or the Source Data file. Source data are provided with this paper.
Code Availability
- Custom R and python scripts for data processing, analysis, and presentation can be found on github at https://github.com/fraenkel-lab/shh-mben.