Author:
Thirant Cécile,Peltier Agathe,Durand Simon,Kramdi Amira,Louis-Brennetot Caroline,Pierre-Eugène Cécile,Costa Ana,Grelier Amandine,Zaïdi Sakina,Gruel Nadège,Jimenez Irène,Lapouble Eve,Pierron Gaëlle,Brisse Hervé J.,Gauthier Arnaud,Fréneaux Paul,Grossetête-Lalami Sandrine,Baudrin Laura G.,Raynal Virginie,Baulande Sylvain,Bellini Angela,Bhalshankar Jaydutt,Carcaboso Angel M.,Geoerger Birgit,Rohrer Hermann,Surdez Didier,Boeva Valentina,Schleiermacher Gudrun,Delattre Olivier,Janoueix-Lerosey Isabelle
Abstract
AbstractTwo cell identities, noradrenergic and mesenchymal, have been characterized in neuroblastoma cell lines according to their epigenetic landscapes relying on specific circuitries of transcription factors. Yet, their relationship and relative contribution in patient tumors remain poorly defined. Here, we demonstrate that the knock-out of GATA3, but not of PHOX2A or PHOX2B, in noradrenergic cells induces a mesenchymal phenotype. Our results document spontaneous plasticity in several models between both identities and show that plasticity relies on epigenetic reprogramming. We demonstrate that an in vivo microenvironment provides a powerful pressure towards a noradrenergic identity for these models. Consistently, tumor cells with a mesenchymal identity are not detected in a series of PDX models. Further study of the intra-tumor noradrenergic heterogeneity reveals two distinct cell populations exhibiting features of chromaffin-like or sympathoblast-like cells. This work emphasizes that both external cues of the environment and intrinsic factors control plasticity and cell identity in neuroblastoma.
Publisher
Cold Spring Harbor Laboratory