The developmental stage of the medulloblastoma cell-of-origin restricts Sonic hedgehog pathway usage and drug sensitivity

Marlinde J Smit; Tosca E I Martini; Inna Armandari; Irena Bočkaj; Walderik W Zomerman; Eduardo S de Camargo Magalhães; Zillah Siragna; Tiny G J Meeuwsen; Frank J G Scherpen; Mirthe H Schoots; Martha Ritsema; Wilfred F A den Dunnen; Eelco W Hoving; Judith T M L Paridaen; Gerald de Haan; Victor Guryev; Sophia W M Bruggeman

doi:10.1242/jcs.258608

The developmental stage of the medulloblastoma cell-of-origin restricts Sonic hedgehog pathway usage and drug sensitivity

Marlinde J Smit, Tosca E I Martini, Inna Armandari, Irena Bočkaj, Walderik W Zomerman, Eduardo S de Camargo Magalhães, Zillah Siragna, Tiny G J Meeuwsen, Frank J G Scherpen, Mirthe H Schoots, Martha Ritsema, Wilfred F A den Dunnen, Eelco W Hoving, Judith T M L Paridaen, Gerald de Haan, Victor Guryev, Sophia W M Bruggeman

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Abstract

Sonic hedgehog (SHH) medulloblastoma originates from the cerebellar granule neuron progenitor (CGNP) lineage, which depends on Hedgehog signaling for its perinatal expansion. Whereas SHH tumors exhibit overall deregulation of this pathway, they also show patient age-specific aberrations. To investigate whether the developmental stage of the CGNP can account for these age-specific lesions, we analyzed developing murine CGNP transcriptomes and observed highly dynamic gene expression as a function of age. Cross-species comparison with human SHH medulloblastoma showed partial maintenance of these expression patterns, and highlighted low primary cilium expression as hallmark of infant medulloblastoma and early embryonic CGNPs. This coincided with reduced responsiveness to upstream SHH pathway component Smoothened, whereas sensitivity to downstream components SUFU and GLI family proteins was retained. Together, these findings can explain the preference for SUFU mutations in infant medulloblastoma and suggest that drugs targeting the downstream SHH pathway will be most appropriate for infant patients.

Original language	English
Article number	jcs258608
Journal	Journal of cell science
Volume	135
Issue number	11
DOIs	https://doi.org/10.1242/jcs.258608
Publication status	Published - 1 Jun 2022

Keywords

Cerebellar development
Cerebellar granule neuron progenitors
Medulloblastoma
Primary cilia
Sonic hedgehog signaling
Tumor cell-of-origin

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Smit, M. J., Martini, T. E. I., Armandari, I., Bočkaj, I., Zomerman, W. W., de Camargo Magalhães, E. S., Siragna, Z., Meeuwsen, T. G. J., Scherpen, F. J. G., Schoots, M. H., Ritsema, M., den Dunnen, W. F. A., Hoving, E. W., Paridaen, J. T. M. L., de Haan, G., Guryev, V., & Bruggeman, S. W. M. (2022). The developmental stage of the medulloblastoma cell-of-origin restricts Sonic hedgehog pathway usage and drug sensitivity. Journal of cell science, 135(11), Article jcs258608. https://doi.org/10.1242/jcs.258608

@article{96534434b89c43f8a061e1d026f03c36,

title = "The developmental stage of the medulloblastoma cell-of-origin restricts Sonic hedgehog pathway usage and drug sensitivity",

abstract = "Sonic hedgehog (SHH) medulloblastoma originates from the cerebellar granule neuron progenitor (CGNP) lineage, which depends on Hedgehog signaling for its perinatal expansion. Whereas SHH tumors exhibit overall deregulation of this pathway, they also show patient age-specific aberrations. To investigate whether the developmental stage of the CGNP can account for these age-specific lesions, we analyzed developing murine CGNP transcriptomes and observed highly dynamic gene expression as a function of age. Cross-species comparison with human SHH medulloblastoma showed partial maintenance of these expression patterns, and highlighted low primary cilium expression as hallmark of infant medulloblastoma and early embryonic CGNPs. This coincided with reduced responsiveness to upstream SHH pathway component Smoothened, whereas sensitivity to downstream components SUFU and GLI family proteins was retained. Together, these findings can explain the preference for SUFU mutations in infant medulloblastoma and suggest that drugs targeting the downstream SHH pathway will be most appropriate for infant patients.",

keywords = "Cerebellar development, Cerebellar granule neuron progenitors, Medulloblastoma, Primary cilia, Sonic hedgehog signaling, Tumor cell-of-origin",

author = "Smit, {Marlinde J} and Martini, {Tosca E I} and Inna Armandari and Irena Bo{\v c}kaj and Zomerman, {Walderik W} and {de Camargo Magalh{\~a}es}, {Eduardo S} and Zillah Siragna and Meeuwsen, {Tiny G J} and Scherpen, {Frank J G} and Schoots, {Mirthe H} and Martha Ritsema and {den Dunnen}, {Wilfred F A} and Hoving, {Eelco W} and Paridaen, {Judith T M L} and {de Haan}, Gerald and Victor Guryev and Bruggeman, {Sophia W M}",

note = "Funding Information: This work was funded by the UMCG Kanker Researchfonds (KRF), a Stichting De Cock-Hadders grant to M.S.; an Indonesian Endowment Fund for Education (LPDP) grant (20151022024475) to I.A.; a Coordena{\c c}a{\~o} de Aperfei{\c c}oamento de Pessoal de Nı{\'v} el Superior, Brasil, CAPES, grant, Finance Code 001 to E.C.M.; a Rosalind Franklin fellowship from the University of Groningen and European Union to J.P.; a Mouse Clinic for Cancer and Ageing/Large Infrastructure grant from the Netherlands Organisation for Scientific Research (NWO) to G.H., a Stichting Vrienden Beatrix Kinderziekenhuis grant, a Rosalind Franklin fellowship from the University of Groningen, and a KWF Kankerbestrijding Cancer Research career award (RUG 2014-6903) to S.B. Open Access funding provided by University Medical Center Groningen (Universitair Medisch Centrum Groningen). Deposited in PMC for immediate release. Publisher Copyright: {\textcopyright} 2022 Company of Biologists Ltd. All rights reserved.",

year = "2022",

month = jun,

day = "1",

doi = "10.1242/jcs.258608",

language = "English",

volume = "135",

journal = "Journal of cell science",

issn = "0021-9533",

publisher = "Company of Biologists Ltd",

number = "11",

}

Smit, MJ, Martini, TEI, Armandari, I, Bočkaj, I, Zomerman, WW, de Camargo Magalhães, ES, Siragna, Z, Meeuwsen, TGJ, Scherpen, FJG, Schoots, MH, Ritsema, M, den Dunnen, WFA, Hoving, EW, Paridaen, JTML, de Haan, G, Guryev, V & Bruggeman, SWM 2022, 'The developmental stage of the medulloblastoma cell-of-origin restricts Sonic hedgehog pathway usage and drug sensitivity', Journal of cell science, vol. 135, no. 11, jcs258608. https://doi.org/10.1242/jcs.258608

TY - JOUR

T1 - The developmental stage of the medulloblastoma cell-of-origin restricts Sonic hedgehog pathway usage and drug sensitivity

AU - Smit, Marlinde J

AU - Martini, Tosca E I

AU - Armandari, Inna

AU - Bočkaj, Irena

AU - Zomerman, Walderik W

AU - de Camargo Magalhães, Eduardo S

AU - Siragna, Zillah

AU - Meeuwsen, Tiny G J

AU - Scherpen, Frank J G

AU - Schoots, Mirthe H

AU - Ritsema, Martha

AU - den Dunnen, Wilfred F A

AU - Hoving, Eelco W

AU - Paridaen, Judith T M L

AU - de Haan, Gerald

AU - Guryev, Victor

AU - Bruggeman, Sophia W M

N1 - Funding Information: This work was funded by the UMCG Kanker Researchfonds (KRF), a Stichting De Cock-Hadders grant to M.S.; an Indonesian Endowment Fund for Education (LPDP) grant (20151022024475) to I.A.; a Coordenaçaõ de Aperfeiçoamento de Pessoal de Nıv́ el Superior, Brasil, CAPES, grant, Finance Code 001 to E.C.M.; a Rosalind Franklin fellowship from the University of Groningen and European Union to J.P.; a Mouse Clinic for Cancer and Ageing/Large Infrastructure grant from the Netherlands Organisation for Scientific Research (NWO) to G.H., a Stichting Vrienden Beatrix Kinderziekenhuis grant, a Rosalind Franklin fellowship from the University of Groningen, and a KWF Kankerbestrijding Cancer Research career award (RUG 2014-6903) to S.B. Open Access funding provided by University Medical Center Groningen (Universitair Medisch Centrum Groningen). Deposited in PMC for immediate release. Publisher Copyright: © 2022 Company of Biologists Ltd. All rights reserved.

PY - 2022/6/1

Y1 - 2022/6/1

N2 - Sonic hedgehog (SHH) medulloblastoma originates from the cerebellar granule neuron progenitor (CGNP) lineage, which depends on Hedgehog signaling for its perinatal expansion. Whereas SHH tumors exhibit overall deregulation of this pathway, they also show patient age-specific aberrations. To investigate whether the developmental stage of the CGNP can account for these age-specific lesions, we analyzed developing murine CGNP transcriptomes and observed highly dynamic gene expression as a function of age. Cross-species comparison with human SHH medulloblastoma showed partial maintenance of these expression patterns, and highlighted low primary cilium expression as hallmark of infant medulloblastoma and early embryonic CGNPs. This coincided with reduced responsiveness to upstream SHH pathway component Smoothened, whereas sensitivity to downstream components SUFU and GLI family proteins was retained. Together, these findings can explain the preference for SUFU mutations in infant medulloblastoma and suggest that drugs targeting the downstream SHH pathway will be most appropriate for infant patients.

AB - Sonic hedgehog (SHH) medulloblastoma originates from the cerebellar granule neuron progenitor (CGNP) lineage, which depends on Hedgehog signaling for its perinatal expansion. Whereas SHH tumors exhibit overall deregulation of this pathway, they also show patient age-specific aberrations. To investigate whether the developmental stage of the CGNP can account for these age-specific lesions, we analyzed developing murine CGNP transcriptomes and observed highly dynamic gene expression as a function of age. Cross-species comparison with human SHH medulloblastoma showed partial maintenance of these expression patterns, and highlighted low primary cilium expression as hallmark of infant medulloblastoma and early embryonic CGNPs. This coincided with reduced responsiveness to upstream SHH pathway component Smoothened, whereas sensitivity to downstream components SUFU and GLI family proteins was retained. Together, these findings can explain the preference for SUFU mutations in infant medulloblastoma and suggest that drugs targeting the downstream SHH pathway will be most appropriate for infant patients.

KW - Cerebellar development

KW - Cerebellar granule neuron progenitors

KW - Medulloblastoma

KW - Primary cilia

KW - Sonic hedgehog signaling

KW - Tumor cell-of-origin

UR - http://www.scopus.com/inward/record.url?scp=85133201705&partnerID=8YFLogxK

U2 - 10.1242/jcs.258608

DO - 10.1242/jcs.258608

M3 - Article

C2 - 35535520

SN - 0021-9533

VL - 135

JO - Journal of cell science

JF - Journal of cell science

IS - 11

M1 - jcs258608

ER -

The developmental stage of the medulloblastoma cell-of-origin restricts Sonic hedgehog pathway usage and drug sensitivity

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