Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups [bulkRNAseq_ATRT_cellLines]

Atypical teratoid rhabdoid tumors (ATRT) are divided into MYC, TYR and SHH subgroups, suggesting diverse lineages of origin. Here, we investigate the imaging of human ATRT at diagnosisand the precise anatomic origin of brain tumors in the Rosa26; Cre-ERT2::Smarcb1flox/flox model. This cross-species analysis points to an extra-cerebral origin for MYC tumors. Additionally, we clearly distinguish SHH ATRT emerging from the cerebellar anterior lobe (CAL) from those emerging from the basal ganglia (BG) and intra-ventricular (IV) regions. Molecular characteristics point to the midbrain-hindbrain boundary as the origin of CAL SHH ATRT, and to the ganglionic eminence as the origin of BG/IV SHH ATRT. Single-cell RNA sequencing on SHH ATRT supports these hypotheses. Trajectory analyses suggest that SMARCB1 loss induces a de-differentiation process mediated by repressors of the neuronal program such as REST, ID and the NOTCH pathway. Overall design: To try to understand how NOTCH pathway could actually participate to cell reprogrammation, we treated two SHH ATRT cell lines (CHLA-02, and IC-032) with DAPT, a gamma secretase inhibitor. 3 independant samples of CHLA-02-ATRT and IC-032 cells were treated with DMSO or DAPT at 10 µM for 7 days. Experiment was designed with 3 replicates for each condition and each cell line.