ScRNAseq dataset from neuroblastomas tumoroids

ABSTRACT: Neuroblastoma (NB), a pediatric cancer arising from disrupted sympathetic neuron differentiation, exhibits marked heterogeneity and limited therapeutic options. To better understand its molecular circuitry dynamics, we applied CARDAMOM, a novel Gene Regulatory Network (GRN) inference framework to single-cell RNA-seq data from patient-derived tumoroids. This approach models gene regulation via piecewise deterministic Markov processes, capturing transcriptional bursting and protein-mediated feedback, overcoming limitations of RNA velocity (e.g., gene independence and lack of biological time). We identified a continuous chromaffin-to-sympathoblast differentiation trajectory, validated by RNA velocity and scFates. Using velocity pseudotime, we selected 85 dynamically relevant genes enriched in cell cycle and DNA replication functions. Notably, 9 genes overlapped with those driving normal sympathoadrenal differentiation, underscoring tumor-normal similarity. The inferred 85-genes network reproduced quite well experimental gene expression patterns in silico, and allowed to predict protein-level dynamics. Furthermore, it allowed to assess the effect of in silico perturbations (both knock-out and overexpression) of hub genes (e.g., TCF4 and PLK1). We show that those perturbations significantly altered cell fate proportions, with TCF4 knockout increasing chromaffin-like cells and reducing proliferative late sympathoblasts — suggesting a therapeutic strategy to promote differentiation. Our work therefore demonstrates that NB tumoroids retain a dynamic, differentiation-like architecture amenable to GRN modeling. Predicted druggable targets (e.g., PLK1, TCF4) offer testable therapeutic avenues, including repurposing BET inhibitors (JQ1) or PLK1 inhibitors (BI2536), potentially in combination.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER: Olivier Gandrillon 

PROVIDER: E-MTAB-16741 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress