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

Autor:	Smit MJ; European Research Institute for the Biology of Ageing/ERIBA, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Martini TEI; European Research Institute for the Biology of Ageing/ERIBA, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Armandari I; European Research Institute for the Biology of Ageing/ERIBA, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Bočkaj I; European Research Institute for the Biology of Ageing/ERIBA, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Zomerman WW; Department of Pediatrics/Pediatric Oncology and Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., de Camargo Magalhães ES; European Research Institute for the Biology of Ageing/ERIBA, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.; Glial Cell Biology Laboratory, Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro, 21949-590, Brazil., Siragna Z; European Research Institute for the Biology of Ageing/ERIBA, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Meeuwsen TGJ; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Scherpen FJG; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Schoots MH; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Ritsema M; European Research Institute for the Biology of Ageing/ERIBA, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., den Dunnen WFA; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Hoving EW; Princess Máxima Center for Pediatric Oncology, Lundlaan 6, 3584 EA Utrecht, The Netherlands., Paridaen JTML; European Research Institute for the Biology of Ageing/ERIBA, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., de Haan G; European Research Institute for the Biology of Ageing/ERIBA, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Guryev V; European Research Institute for the Biology of Ageing/ERIBA, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Bruggeman SWM; European Research Institute for the Biology of Ageing/ERIBA, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.
Jazyk:	angličtina
Zdroj:	Journal of cell science [J Cell Sci] 2022 Jun 01; Vol. 135 (11). Date of Electronic Publication: 2022 Jun 08.
DOI:	10.1242/jcs.258608
Abstrakt:	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. Competing Interests: Competing interests The authors declare no competing or financial interests. (© 2022. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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