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

Author:

Smit Marlinde J.1ORCID,Martini Tosca E. I.1ORCID,Armandari Inna1ORCID,Bočkaj Irena1ORCID,Zomerman Walderik W.2ORCID,de Camargo Magalhães Eduardo S.13ORCID,Siragna Zillah1ORCID,Meeuwsen Tiny G. J.4,Scherpen Frank J. G.4,Schoots Mirthe H.4ORCID,Ritsema Martha1ORCID,den Dunnen Wilfred F. A.4ORCID,Hoving Eelco W.5ORCID,Paridaen Judith T. M. L.1ORCID,de Haan Gerald1ORCID,Guryev Victor1ORCID,Bruggeman Sophia W. M.1ORCID

Affiliation:

1. European Research Institute for the Biology of Ageing/ERIBA, University Medical Center Groningen, University of Groningen 1 , Hanzeplein 1, 9700 RB, Groningen , The Netherlands

2. University Medical Center Groningen, University of Groningen 2 Department of Pediatrics/Pediatric Oncology and Hematology , , Hanzeplein 1, 9700 RB, Groningen , The Netherlands

3. Biomedical Sciences Institute, Federal University of Rio de Janeiro 3 Glial Cell Biology Laboratory , , Rio de Janeiro, 21949-590 , Brazil

4. University Medical Center Groningen, University of Groningen 4 Department of Pathology and Medical Biology , , Hanzeplein 1, 9700 RB, Groningen , The Netherlands

5. Princess Máxima Center for Pediatric Oncology 5 , Lundlaan 6, 3584 EA Utrecht , The Netherlands

Abstract

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.

Funder

UMCG Kanker Researchfonds

Stichting De Cock-Hadders

Indonesian Endowment Fund for Education

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

University of Groningen

European Union

Netherlands Organisation for Scientific Research

Stichting Vrienden Beatrix Kinderziekenhuis

KWF Kankerbestrijding

Universitair Medisch Centrum Groningen

Publisher

The Company of Biologists

Subject

Cell Biology

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