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

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-ReyaJill P. Mesirov, Andrey Korshunov, Kristian W. Pajtler, Scott L. Pomeroy, Olivier Ayrault, Shawn M. Davidson, Jennifer A. Cotter, Michael D. Taylor, Ernest Fraenkel^*

^*Corresponding author for this work

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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.

Original language	English (US)
Article number	270
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-44300-0
State	Published - Dec 2024

Funding

This study was funded by U01-CA184898 (E.F, J.P.M., S.L.P.), U01-CA253547 (J.P.M., E.F., R.W.R.), R01-NS089076 (E.F.), P50-HD105351 (S.L.P.), R35-NS122339 (R.W.R.), U24-CA220341 (J.P.M.), R01-NS106155 (M.D.T.), R01-CA159859 (M.D.T.), R01-CA255369 (M.D.T.), SU2C-AACR-DT1113 (M.D.T.), SU2C-AACR-DT-19-15 (M.D.T.), SU2C - Convergence 3.14 (S.M.D.), M.I.T. Takeda Fellowship (M.P.G.), Robert J. Arceci Innovation Award from St. Baldrick’s Foundation (OA), PEDIAC consortium, INCA_15670 (OA), and INCa PRTK-19-027 (CD/OA). Additionally, M.D.T. is supported by The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, The Canadian Institutes of Health Research, The Cure Search Foundation, Matthew Larson Foundation (IronMatt), b.r.a.i.n.child, Meagan’s Walk, SWIFTY Foundation, The Brain Tumour Charity, Genome Canada, Genome BC, Genome Quebec, the Ontario Research Fund, Worldwide Cancer Research, V-Foundation for Cancer Research, and the Ontario Institute for Cancer Research through funding provided by the Government of Ontario, Canadian Cancer Society Research Institute Impact grant, a Cancer Research UK Brain Tumour Award, and the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto. D.R.G. was supported with personal grants by the German Academic Scholarship Foundation (Studienstiftung des Deutschen Volkes) and the Mildred Scheel Doctoral Fellowship program of the German Cancer Aid (Deutsche Krebshilfe). DRG and KWP are thankful to the non-profit foundation Ein Kiwi gegen Krebs for their support. We also thank Yoon-Jae Cho, John Michaels, Koei Chin, Joe Gray, Connie New, and Ali Abdullatif for their help with the manuscript. Additionally, we appreciate support from the USC Norris Comprehensive Cancer Center Translational Pathology Core (P30CA014089), the Pediatric Research Biorepository at CHLA, and the Histology Core at the Koch Institute at MIT.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-023-44300-0

Cite this

Gold, M. P., Ong, W., Masteller, A. M., Ghasemi, D. R., Galindo, J. A., Park, N. R., Huynh, N. C., Donde, A., Pister, V., Saurez, R. A., Vladoiu, M. C., Hwang, G. H., Eisemann, T., Donovan, L. K., Walker, A. D., Benetatos, J., Dufour, C., Garzia, L., Segal, R. A., ... Fraenkel, E. (2024). Developmental basis of SHH medulloblastoma heterogeneity. Nature communications, 15(1), Article 270. https://doi.org/10.1038/s41467-023-44300-0

@article{6579154c7d854a63b3c85fa99882ad89,

title = "Developmental basis of SHH medulloblastoma heterogeneity",

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.",

author = "Gold, {Maxwell P.} and Winnie Ong and Masteller, {Andrew M.} and Ghasemi, {David R.} and Galindo, {Julie Anne} and Park, {Noel R.} and Huynh, {Nhan C.} and Aneesh Donde and Veronika Pister and Saurez, {Raul A.} and Vladoiu, {Maria C.} and Hwang, {Grace H.} and Tanja Eisemann and Donovan, {Laura K.} and Walker, {Adam D.} and Joseph Benetatos and Christelle Dufour and Livia Garzia and Segal, {Rosalind A.} and Wechsler-Reya, {Robert J.} and Mesirov, {Jill P.} and Andrey Korshunov and Pajtler, {Kristian W.} and Pomeroy, {Scott L.} and Olivier Ayrault and Davidson, {Shawn M.} and Cotter, {Jennifer A.} and Taylor, {Michael D.} and Ernest Fraenkel",

note = "Publisher Copyright: {\textcopyright} 2024, The Author(s).",

year = "2024",

month = dec,

doi = "10.1038/s41467-023-44300-0",

language = "English (US)",

volume = "15",

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Gold, MP, Ong, W, Masteller, AM, Ghasemi, DR, Galindo, JA, Park, NR, Huynh, NC, Donde, A, Pister, V, Saurez, RA, Vladoiu, MC, Hwang, GH, Eisemann, T, Donovan, LK, Walker, AD, Benetatos, J, Dufour, C, Garzia, L, Segal, RA, Wechsler-Reya, RJ, Mesirov, JP, Korshunov, A, Pajtler, KW, Pomeroy, SL, Ayrault, O, Davidson, SM, Cotter, JA, Taylor, MD & Fraenkel, E 2024, 'Developmental basis of SHH medulloblastoma heterogeneity', Nature communications, vol. 15, no. 1, 270. https://doi.org/10.1038/s41467-023-44300-0

TY - JOUR

T1 - Developmental basis of SHH medulloblastoma heterogeneity

AU - Gold, Maxwell P.

AU - Ong, Winnie

AU - Masteller, Andrew M.

AU - Ghasemi, David R.

AU - Galindo, Julie Anne

AU - Park, Noel R.

AU - Huynh, Nhan C.

AU - Donde, Aneesh

AU - Pister, Veronika

AU - Saurez, Raul A.

AU - Vladoiu, Maria C.

AU - Hwang, Grace H.

AU - Eisemann, Tanja

AU - Donovan, Laura K.

AU - Walker, Adam D.

AU - Benetatos, Joseph

AU - Dufour, Christelle

AU - Garzia, Livia

AU - Segal, Rosalind A.

AU - Wechsler-Reya, Robert J.

AU - Mesirov, Jill P.

AU - Korshunov, Andrey

AU - Pajtler, Kristian W.

AU - Pomeroy, Scott L.

AU - Ayrault, Olivier

AU - Davidson, Shawn M.

AU - Cotter, Jennifer A.

AU - Taylor, Michael D.

AU - Fraenkel, Ernest

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-023-44300-0

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VL - 15

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 270

ER -

Developmental basis of SHH medulloblastoma heterogeneity

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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