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

doi:10.1038/s41467-023-44300-0

Developmental basis of SHH medulloblastoma heterogeneity

Nat Commun. 2024 Jan 8;15(1):270. doi: 10.1038/s41467-023-44300-0.

Authors

Maxwell P Gold¹, Winnie Ong^{2

3}, Andrew M Masteller¹, David R Ghasemi^{4

5

6}, Julie Anne Galindo⁷, Noel R Park^{8

9

10}, Nhan C Huynh¹, Aneesh Donde¹, Veronika Pister¹, Raul A Saurez², Maria C Vladoiu², Grace H Hwang^{11

12}, Tanja Eisemann¹³, Laura K Donovan^{2

14}, Adam D Walker⁷, Joseph Benetatos¹, Christelle Dufour^{15

16}, Livia Garzia^{17

18}, Rosalind A Segal^{11

12}, Robert J Wechsler-Reya^{13

19

20}, Jill P Mesirov²¹, Andrey Korshunov^{4

22

23

24}, Kristian W Pajtler^{4

5

6}, Scott L Pomeroy^{25

26

27}, Olivier Ayrault^{28

29}, Shawn M Davidson^{8

30

31}, Jennifer A Cotter^{7

32}, Michael D Taylor^{2

3

14

33

34

35

36

37}, Ernest Fraenkel^{38

39}

Affiliations

¹ Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
² Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
³ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
⁴ Hopp-Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
⁵ Division of Pediatric Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶ Department of Pediatric Oncology, Hematology, and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
⁷ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles (CHLA), Los Angeles, CA, USA.
⁸ Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
⁹ Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
¹⁰ Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA.
¹¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹² Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
¹³ Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
¹⁴ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁵ Department of Child and Adolescent Oncology, Gustave Roussy, Villejuif, France.
¹⁶ INSERM U981, Molecular Predictors and New Targets in Oncology, University Paris-Saclay, Villejuif, France.
¹⁷ Cancer Research Program, McGill University, Montreal, QC, Canada.
¹⁸ MUHC Research Institute, McGill University, Montreal, QC, Canada.
¹⁹ Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
²⁰ Department of Neurology, Columbia University Medical Center, New York, NY, USA.
²¹ Department of Medicine, Moores Cancer Center, UC San Diego, La Jolla, CA, USA.
²² Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²³ German Cancer Consortium (DKTK), Heidelberg, Germany.
²⁴ Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
²⁵ Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
²⁶ Harvard Medical School, Boston, MA, USA.
²⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁸ Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France.
²⁹ Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France.
³⁰ Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
³¹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
³² Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³³ Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.
³⁴ Department of Surgery, University of Toronto, Toronto, ON, Canada.
³⁵ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
³⁶ Texas Children's Cancer Center, Hematology-Oncology Section, Houston, TX, USA.
³⁷ Department of Pediatrics - Hematology/Oncology and Neurosurgery, Baylor College of Medicine, Houston, TX, USA.
³⁸ Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. fraenkel-admin@mit.edu.
³⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. fraenkel-admin@mit.edu.

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.

MeSH terms

Cerebellar Neoplasms* / genetics
Cerebellum
Hedgehog Proteins / genetics
Humans
Medulloblastoma* / genetics
Proteomics

Substances

Hedgehog Proteins
SHH protein, human

Abstract

MeSH terms

Substances

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