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Developmental basis of SHH medulloblastoma heterogeneity

Author

Listed:
  • Maxwell P. Gold

    (Massachusetts Institute of Technology (MIT))

  • Winnie Ong

    (The Hospital for Sick Children
    University of Toronto)

  • Andrew M. Masteller

    (Massachusetts Institute of Technology (MIT))

  • David R. Ghasemi

    (Hopp-Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Julie Anne Galindo

    (Children’s Hospital Los Angeles (CHLA))

  • Noel R. Park

    (Princeton University
    Princeton University
    Princeton University)

  • Nhan C. Huynh

    (Massachusetts Institute of Technology (MIT))

  • Aneesh Donde

    (Massachusetts Institute of Technology (MIT))

  • Veronika Pister

    (Massachusetts Institute of Technology (MIT))

  • Raul A. Saurez

    (The Hospital for Sick Children)

  • Maria C. Vladoiu

    (The Hospital for Sick Children)

  • Grace H. Hwang

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Tanja Eisemann

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Laura K. Donovan

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Adam D. Walker

    (Children’s Hospital Los Angeles (CHLA))

  • Joseph Benetatos

    (Massachusetts Institute of Technology (MIT))

  • Christelle Dufour

    (Gustave Roussy
    University Paris-Saclay)

  • Livia Garzia

    (McGill University
    McGill University)

  • Rosalind A. Segal

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Robert J. Wechsler-Reya

    (Sanford Burnham Prebys Medical Discovery Institute
    Columbia University Medical Center
    Columbia University Medical Center)

  • Jill P. Mesirov

    (Moores Cancer Center, UC San Diego)

  • Andrey Korshunov

    (Hopp-Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK)
    Heidelberg University Hospital)

  • Kristian W. Pajtler

    (Hopp-Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Scott L. Pomeroy

    (Boston Children’s Hospital
    Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Olivier Ayrault

    (PSL Research University
    Université Paris-Saclay, CNRS UMR 3347)

  • Shawn M. Davidson

    (Princeton University
    Rutgers Cancer Institute of New Jersey
    Northwestern University)

  • Jennifer A. Cotter

    (Children’s Hospital Los Angeles (CHLA)
    University of Southern California)

  • Michael D. Taylor

    (The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children
    The Hospital for Sick Children)

  • Ernest Fraenkel

    (Massachusetts Institute of Technology (MIT)
    Broad Institute of MIT and Harvard)

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.

Suggested Citation

  • 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, 2024. "Developmental basis of SHH medulloblastoma heterogeneity," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44300-0
    DOI: 10.1038/s41467-023-44300-0
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    References listed on IDEAS

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