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 and Ernest Fraenkel ()
Additional contact information
Maxwell P. Gold: Massachusetts Institute of Technology (MIT)
Winnie Ong: The Hospital for Sick Children
Andrew M. Masteller: Massachusetts Institute of Technology (MIT)
David R. Ghasemi: Hopp-Children’s Cancer Center Heidelberg (KiTZ)
Julie Anne Galindo: Children’s Hospital Los Angeles (CHLA)
Noel R. Park: 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
Tanja Eisemann: Sanford Burnham Prebys Medical Discovery Institute
Laura K. Donovan: 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
Livia Garzia: McGill University
Rosalind A. Segal: Dana-Farber Cancer Institute
Robert J. Wechsler-Reya: Sanford Burnham Prebys Medical Discovery Institute
Jill P. Mesirov: 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: Boston Children’s Hospital
Olivier Ayrault: PSL Research University
Shawn M. Davidson: Princeton University
Jennifer A. Cotter: Children’s Hospital Los Angeles (CHLA)
Michael D. Taylor: The Hospital for Sick Children
Ernest Fraenkel: Massachusetts Institute of Technology (MIT)

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-023-44300-0

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