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.

The role of developmental pathways in medulloblastoma tumours (MB) with sonic hedgehog (SHH) activation remains to be explored. Here, the authors perform multi-omic analysis and characterise the key transcriptomic and metabolic patterns of highly differentiated cells in SHH MBs.

Details

Title
Developmental basis of SHH medulloblastoma heterogeneity
Author
Gold, Maxwell P. 1 ; Ong, Winnie 2 ; Masteller, Andrew M. 1 ; Ghasemi, David R. 3   VIAFID ORCID Logo  ; Galindo, Julie Anne 4 ; Park, Noel R. 5   VIAFID ORCID Logo  ; Huynh, Nhan C. 1 ; Donde, Aneesh 1 ; Pister, Veronika 1   VIAFID ORCID Logo  ; Saurez, Raul A. 6 ; Vladoiu, Maria C. 6 ; Hwang, Grace H. 7 ; Eisemann, Tanja 8   VIAFID ORCID Logo  ; Donovan, Laura K. 9 ; Walker, Adam D. 4 ; Benetatos, Joseph 1   VIAFID ORCID Logo  ; Dufour, Christelle 10   VIAFID ORCID Logo  ; Garzia, Livia 11   VIAFID ORCID Logo  ; Segal, Rosalind A. 7   VIAFID ORCID Logo  ; Wechsler-Reya, Robert J. 12 ; Mesirov, Jill P. 13   VIAFID ORCID Logo  ; Korshunov, Andrey 14 ; Pajtler, Kristian W. 3   VIAFID ORCID Logo  ; Pomeroy, Scott L. 15 ; Ayrault, Olivier 16   VIAFID ORCID Logo  ; Davidson, Shawn M. 17   VIAFID ORCID Logo  ; Cotter, Jennifer A. 18   VIAFID ORCID Logo  ; Taylor, Michael D. 19   VIAFID ORCID Logo  ; Fraenkel, Ernest 20   VIAFID ORCID Logo 

1  Massachusetts Institute of Technology (MIT), Department of Biological Engineering, Cambridge, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786) 
2  The Hospital for Sick Children, Developmental & Stem Cell Biology Program, Toronto, Canada (GRID:grid.430185.b); University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
3  Hopp-Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany (GRID:grid.510964.f); German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Division of Pediatric Neuro-oncology, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); Heidelberg University Hospital, Department of Pediatric Oncology, Hematology, and Immunology, Heidelberg, Germany (GRID:grid.5253.1) (ISNI:0000 0001 0328 4908) 
4  Children’s Hospital Los Angeles (CHLA), Department of Pathology and Laboratory Medicine, Los Angeles, USA (GRID:grid.239546.f) (ISNI:0000 0001 2153 6013) 
5  Princeton University, Lewis-Sigler Institute for Integrative Genomics, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006); Princeton University, Department of Molecular Biology, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006); Princeton University, Ludwig Institute for Cancer Research, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006) 
6  The Hospital for Sick Children, Developmental & Stem Cell Biology Program, Toronto, Canada (GRID:grid.430185.b) 
7  Dana-Farber Cancer Institute, Department of Cancer Biology, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910); Harvard Medical School, Department of Neurobiology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
8  Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, La Jolla, USA (GRID:grid.479509.6) (ISNI:0000 0001 0163 8573) 
9  The Hospital for Sick Children, Developmental & Stem Cell Biology Program, Toronto, Canada (GRID:grid.430185.b); The Hospital for Sick Children, The Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Canada (GRID:grid.430185.b) 
10  Gustave Roussy, Department of Child and Adolescent Oncology, Villejuif, France (GRID:grid.14925.3b) (ISNI:0000 0001 2284 9388); University Paris-Saclay, INSERM U981, Molecular Predictors and New Targets in Oncology, Villejuif, France (GRID:grid.460789.4) (ISNI:0000 0004 4910 6535) 
11  McGill University, Cancer Research Program, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649); McGill University, MUHC Research Institute, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649) 
12  Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, La Jolla, USA (GRID:grid.479509.6) (ISNI:0000 0001 0163 8573); Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675); Columbia University Medical Center, Department of Neurology, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675) 
13  Moores Cancer Center, UC San Diego, Department of Medicine, La Jolla, USA (GRID:grid.516081.b) (ISNI:0000 0000 9217 9714) 
14  Hopp-Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany (GRID:grid.510964.f); German Cancer Research Center (DKFZ), Clinical Cooperation Unit Neuropathology (B300), Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); German Cancer Consortium (DKTK), Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); Heidelberg University Hospital, Department of Neuropathology, Heidelberg, Germany (GRID:grid.5253.1) (ISNI:0000 0001 0328 4908) 
15  Boston Children’s Hospital, Department of Neurology, Boston, USA (GRID:grid.2515.3) (ISNI:0000 0004 0378 8438); Harvard Medical School, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) 
16  PSL Research University, Institut Curie, Orsay, France (GRID:grid.440907.e) (ISNI:0000 0004 1784 3645); Université Paris-Saclay, CNRS UMR 3347, Orsay, France (GRID:grid.460789.4) (ISNI:0000 0004 4910 6535) 
17  Princeton University, Lewis-Sigler Institute for Integrative Genomics, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006); Rutgers Cancer Institute of New Jersey, New Brunswick, USA (GRID:grid.16750.35) (ISNI:0000 0004 0405 0718); Northwestern University, Division of Pulmonary and Critical Care Medicine, Department of Medicine, The Feinberg School of Medicine, Chicago, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507) 
18  Children’s Hospital Los Angeles (CHLA), Department of Pathology and Laboratory Medicine, Los Angeles, USA (GRID:grid.239546.f) (ISNI:0000 0001 2153 6013); University of Southern California, Department of Pathology, Keck School of Medicine, Los Angeles, USA (GRID:grid.42505.36) (ISNI:0000 0001 2156 6853) 
19  The Hospital for Sick Children, Developmental & Stem Cell Biology Program, Toronto, Canada (GRID:grid.430185.b); University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); The Hospital for Sick Children, The Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Canada (GRID:grid.430185.b); The Hospital for Sick Children, Division of Neurosurgery, Toronto, Canada (GRID:grid.430185.b); University of Toronto, Department of Surgery, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, Department of Medical Biophysics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); Hematology-Oncology Section, Texas Children’s Cancer Center, Houston, USA (GRID:grid.416986.4) (ISNI:0000 0001 2296 6154); Baylor College of Medicine, Department of Pediatrics – Hematology/Oncology and Neurosurgery, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
20  Massachusetts Institute of Technology (MIT), Department of Biological Engineering, Cambridge, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) 
Pages
270
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-44300-0
ProQuest document ID
2911668099
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.