Defining Neuroblastoma Cell Heterogeneity and Plasticity through in vivo Single-Cell RNA Sequencing

Authors

• S Di Giulio
• M Sun
• Z Liu
• Y Wu
• R Nguyen
• J Shern
• CJ Thiele

Abstract

Neuroblastoma (NB) is a childhood cancer arising from neural crest progenitor cells during the development of the sympathoadrenal nervous system. Two cell subtypes are predominant in NB: an adrenergic (ADRN) population, and a mesenchymal-like (MES). These populations exhibit plasticity, as NB cells can interconvert to adapt to selective pressures, such as chemotherapy. Therefore, comprehending the molecular mechanisms underlying NB plasticity is imperative to improve the prospects of curing relapsed patients.
With in vivo scRNAseq of NB PDX models, we demonstrated that ADRN cells predominated, while MES cells were a rare population within the tumor. However, cells with a MES signature increased in relapsed tumors treated with the combination of temozolomide/irinotecan, raising the possibility that 1) MES cells selectively accumulate at relapse due to their higher chemo-resistance; 2) NB cells interconvert between ADRN/MES states in response to chemotherapies. To distinguish between these two mechanisms, we have performed in vivo scRNAseq on barcoded NB PDX cells. The preliminary results indicate that several barcoded cells initially characterized as ADRN have been re-programmed to a MES phenotype and a new phenotype distinct from ADRN/MES after temozolomide/irinotecan treatment. We plan to use a new tool for single-cell intratumor heterogeneity inference (Trisicell). By combining these approaches, we can track the fate of each NB cell in response to cytotoxic therapy.
These experiments will shed light on the molecular mechanisms underlying NB heterogeneity and plasticity, providing insight into drug resistance and opportunities for new therapeutic approaches for relapsed tumors in NB patients.

Scientific Focus Area: Cancer Biology

This page was last updated on Tuesday, August 6, 2024