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

• DOI: 10.1242/jcs.258608
• Publication Date: 2022-05-10T07:58:34Z
• Authors: Marlinde J. Smit; Tosca E. I. Martini; Inna Armandari; Irena Bočkaj; Walderik W. Zomerman; Eduardo S. de Cam...; Zillah Siragna; Tiny G. J. Meeuwsen; Frank J. G. Scherpen; Mirthe H. Schoots; Martha Ritsema; Wilfred F. A. den...; Eelco W. Hoving; Judith T. M. L. P...; Gerald de Haan; Victor Guryev; Sophia W. M. Brug...
• Keywords: Smoothened; PTCH1

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 developmental stage CGNP can account these lesions, we analyzed developing murine transcriptomes and observed highly dynamic gene expression as a function age. Cross-species comparison with human showed partial maintenance patterns, highlighted low primary cilium hallmark infant early embryonic CGNPs. This coincided reduced responsiveness to upstream pathway component Smoothened, whereas sensitivity downstream components SUFU GLI family proteins was retained. Together, findings explain preference mutations in suggest that drugs targeting will be most appropriate patients.