SOX11 as mediator of the adrenergic cell state in neuroblastoma: towards cell precision medicine

01 November 2019 → 31 December 2021
Research Foundation - Flanders (FWO)
Research disciplines
No data available
Neuroblastoma SOX11 MYCN Adrenergic Mesenchymal Chemo-tolerant cells
Project description

Neuroblastoma (NB) is a pediatric tumor arising from the peripheral nervous system with still poor survival for high-risk patients despite intensive therapy. Recent studies discovered two different phenotypic subpopulations in NB tumors, i.e. so-called adrenergic (ADRN) and neural-crest cell/mesenchymal like (NCC/MES) cells. The latter cell type is more chemo-tolerant and enriched in post-therapy and relapse tumors. We recently identified the neuronal and ADRN specific transcription factor SOX11 to be implicated in NB development. In this research project, I will further unravel the mechanism through which SOX11 contributes to the NB phenotype. I discovered a putative role for SOX11 as an epigenetic regulator by chromatin remodeling and facilitating MYC(N) hijacking of normal transcriptional developmental programs. Therefore, I will combine dedicated methods to unravel these epigenetic alterations (using single-cell RNA-seq, ATAC-seq and ChIP-seq data) upon SOX11 and/or MYCN depletion in NB cells (in vitro) and overexpression in mouse and/or zebrafish tumors (in vivo). I will modulate SOX11 expression in NCC/MES and ADRN like cell types to explore the interchange between these two cellular subtypes and characterize these cell types on single-cell level. In a final step, I will search and evaluate drug combinations to target both the ADRN and NCC/MES cell parts of NB tumors to improve current treatment results by the novel therapeutic concept coined "cell precision medicine".