Abstract

Molecular classification has improved the knowledge of medulloblastoma (MB), the most common malignant brain tumour in children, however current treatments cause severe side effects in patients. Cancer stem cells (CSCs) have been described in MB and represent a sub population characterised by self-renewal and the ability to generate tumour cells, thus representing the reservoir of the tumour. To investigate molecular pathways that characterise this sub population, we isolated CSCs from Sonic Hedgehog Medulloblastoma (SHH MB) arisen in Patched 1 (Ptch1) heterozygous mice, and performed miRNA- and mRNA-sequencing. Comparison of the miRNA-sequencing of SHH MB CSCs with that obtained from cerebellar Neural Stem Cells (NSCs), allowed us to obtain a SHH MB CSC miRNA differential signature. Pathway enrichment analysis in SHH MB CSCs mirnome and transcriptome was performed and revealed a series of enriched pathways. We focused on the putative targets of the SHH MB CSC miRNAs that were involved in the enriched pathways of interest, namely pathways in cancer, PI3k-Akt pathway and protein processing in endoplasmic reticulum pathway. In silico analysis was performed in SHH MB patients and identified several genes, whose expression was associated with worse overall survival of SHH MB patients. This study provides novel candidates whose functional role should be further investigated in SHH MB.

Highlights

  • IntroductionMultimodal aggressive treatments include surgical resection and chemo- and radio-therapy, and are able to cure about 70% of patients

  • Medulloblastoma (MB) is the most common malignant brain tumour in childhood

  • Sonic Hedgehog Medulloblastoma (SHH MB) Cancer stem cells (CSCs) were subjected to small RNA sequencing and miRNA expression levels were compared to our recently published Neural Stem Cells (NSCs) mirnome [26]

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Summary

Introduction

Multimodal aggressive treatments include surgical resection and chemo- and radio-therapy, and are able to cure about 70% of patients. Due to these cytotoxic and aggressive therapies, survivors often face severe side effects. Despite being initially characterised according to histological features, the 2016 WHO consensus conference envisaged five subgroups: Wingless-type MMTV integration site family (WNT) activated, Sonic Hedgehog (SHH) activated P53 wild-type, SHH activated P53 mutant, non-WNT/non-SHH Group 3, non-WNT/non-SHH Group 4 [6]. Research groups continue implementing and integrating molecular and clinical features, and recent reports described up to 12 molecular subtypes that more deeply characterise the 4 subgroups that were originally described by Northcott [4]: WNT has 2 subtypes (α and β), SHH has 4 subtypes (α, β, γ and δ), group 3 and 4 have 3 subtypes each (α, β and γ) [2]

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