Reversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma

Nom de la revue
Nature Communications
Cécile Thirant, Agathe Peltier, Simon Durand, Amira Kramdi, Caroline Louis-Brennetot, Cécile Pierre-Eugène, Margot Gautier, Ana Costa, Amandine Grelier, Sakina Zaïdi, Nadège Gruel, Irène Jimenez, Eve Lapouble, Gaëlle Pierron, Déborah Sitbon, Hervé J. Brisse, Arnaud Gauthier, Paul Fréneaux, Sandrine Grossetête, Laura G. Baudrin, Virginie Raynal, Sylvain Baulande, Angela Bellini, Jaydutt Bhalshankar, Angel M. Carcaboso, Birgit Geoerger, Hermann Rohrer, Didier Surdez, Valentina Boeva, Gudrun Schleiermacher, Olivier Delattre, Isabelle Janoueix-Lerosey

AbstractNoradrenergic and mesenchymal identities have been characterized in neuroblastoma cell lines according to their epigenetic landscapes and core regulatory circuitries. However, their relationship and relative contribution in patient tumors remain poorly defined. We now document spontaneous and reversible plasticity between the two identities, associated with epigenetic reprogramming, in several neuroblastoma models. Interestingly, xenografts with cells from each identity eventually harbor a noradrenergic phenotype suggesting that the microenvironment provides a powerful pressure towards this phenotype. Accordingly, such a noradrenergic cell identity is systematically observed in single-cell RNA-seq of 18 tumor biopsies and 15 PDX models. Yet, a subpopulation of these noradrenergic tumor cells presents with mesenchymal features that are shared with plasticity models, indicating that the plasticity described in these models has relevance in neuroblastoma patients. This work therefore emphasizes that intrinsic plasticity properties of neuroblastoma cells are dependent upon external cues of the environment to drive cell identity.