Nature Communications (Jan 2024)
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
Affiliations
- Maxwell P. Gold
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT)
- Winnie Ong
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children
- Andrew M. Masteller
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT)
- David R. Ghasemi
- Hopp-Children’s Cancer Center Heidelberg (KiTZ)
- Julie Anne Galindo
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles (CHLA)
- Noel R. Park
- Lewis-Sigler Institute for Integrative Genomics, Princeton University
- Nhan C. Huynh
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT)
- Aneesh Donde
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT)
- Veronika Pister
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT)
- Raul A. Saurez
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children
- Maria C. Vladoiu
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children
- Grace H. Hwang
- Department of Cancer Biology, Dana-Farber Cancer Institute
- Tanja Eisemann
- Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute
- Laura K. Donovan
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children
- Adam D. Walker
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles (CHLA)
- Joseph Benetatos
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT)
- Christelle Dufour
- Department of Child and Adolescent Oncology, Gustave Roussy
- Livia Garzia
- Cancer Research Program, McGill University
- Rosalind A. Segal
- Department of Cancer Biology, Dana-Farber Cancer Institute
- Robert J. Wechsler-Reya
- Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute
- Jill P. Mesirov
- Department of Medicine, Moores Cancer Center, UC San Diego
- Andrey Korshunov
- Hopp-Children’s Cancer Center Heidelberg (KiTZ)
- Kristian W. Pajtler
- Hopp-Children’s Cancer Center Heidelberg (KiTZ)
- Scott L. Pomeroy
- Department of Neurology, Boston Children’s Hospital
- Olivier Ayrault
- Institut Curie, PSL Research University
- Shawn M. Davidson
- Lewis-Sigler Institute for Integrative Genomics, Princeton University
- Jennifer A. Cotter
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles (CHLA)
- Michael D. Taylor
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children
- Ernest Fraenkel
- Department of Biological Engineering, Massachusetts Institute of Technology (MIT)
- DOI
- https://doi.org/10.1038/s41467-023-44300-0
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 20
Abstract
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.
