MBRS-28. Single-Cell Transcriptome Analysis of Medulloblastoma

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

“…To study the potential impact of the CGNP developmental age on medulloblastoma outcome, we have taken advantage of a transgenic mouse model that allows the prospective isolation of the entire CGNP cell lineage during embryonic and postnatal development [35,36]. As reported before, we confirmed that CGNPs exhibit dynamic changes in gene expression in time, highlighting the identity changes of the CGNP population as neural development progresses [4,5,35]. We also confirmed that CGNPs resemble human SHH medulloblastoma and importantly, that early embryonic CGNPs co-segregate with the youngest patients, corroborating a linear relationship between cell-of-origin and patient age.…”

“…The idea that naturally occurring changes in identity of the tumor cell lineage-of-origin impact on tumor outcome, is supported by studies showing differences in tumor onset and phenotype in relation to timing of tumor induction, although the type of genetic lesion and intra-tumoral heterogeneity are also expected play a role [4,5,32,[70][71][72][73]. Indeed, when we compared gene expression patterns between developing CGNPs, we found unique enriched biological processes at each developmental stage, and several of those have been linked to SHH medulloblastoma.…”

“…It consists of four main transcriptional subgroups that can be further subdivided upon additional molecular profiling [1][2][3][4][5]. The Sonic Hedgehog (SHH) subgroup of medulloblastoma, which accounts for thirty percent of all medulloblastoma cases, is believed to originate from the cerebellar granule neuron progenitor (CGNP) population that critically depends on Sonic Hedgehog pathway signaling for its perinatal expansion [4][5][6][7][8][9][10][11]. Sonic Hedgehog is a secreted morphogen that controls development and patterning in many organs including the central nervous system [12,13].…”

Downregulation of miR‐326 and its host gene β‐arrestin1 induces pro‐survival activity of E2F1 and promotes medulloblastoma growth

“…As shown in Figure 5A, ARRB1 clearly formed a complex with E2F1 and p300 and this interaction was associated with an appreciable increase in E2F1 acetylation ( Figure 5B). IP experiments were also performed on endogenous proteins in GCPs [65,14], where both ARRB1 and E2F1 are expressed and ARRB1 has been shown to contribute to the coordinated sequence of signaling regulating the proliferation, differentiation, and death of GCPs [26,25]. Supplementary Figure 6 shows the co-immunoprecipitation of ARRB1 and E2F1, accompanied by the acetylation of E2F1.…”

“…We previously identified a subset of microRNAs with remarkably low expression levels in MBs [12,13]. These microRNAs were expressed at low levels in cerebellar granule cell progenitors (GCPs), the proliferating and undifferentiated cells of the developing cerebellum, described as cell of origin of certain MBs [14]. Differentiation of GCPs into cerebellar granule cells was associated with up-regulation of these microRNAs, which contributed to this critical transition by inhibiting proliferative signaling [13].…”