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

• Published in: Journal of cell science Vol. 135; no. 11
• Main Authors: Smit, Marlinde J, Martini, Tosca E I, Armandari, Inna, Bočkaj, Irena, Zomerman, Walderik W, de Camargo Magalhães, Eduardo S, Siragna, Zillah, Meeuwsen, Tiny G J, Scherpen, Frank J G, Schoots, Mirthe H, Ritsema, Martha, den Dunnen, Wilfred F A, Hoving, Eelco W, Paridaen, Judith T M L, de Haan, Gerald, Guryev, Victor, Bruggeman, Sophia W M
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.06.2022
• Subjects: Animals; Cell Biology and Disease; Cell Proliferation - physiology; Cerebellar Neoplasms - drug therapy; Cerebellar Neoplasms - genetics; Cilia and Flagella; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Humans; Medulloblastoma - drug therapy; Medulloblastoma - genetics; Mice; Neural Stem Cells - metabolism; Tumor cell-of-origin; Sonic hedgehog signaling; Primary cilia; Medulloblastoma; Cerebellar development; Cerebellar granule neuron progenitors
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.258608

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.