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

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 and Isabelle Janoueix-Lerosey ()
Additional contact information
Cécile Thirant: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Agathe Peltier: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Simon Durand: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Amira Kramdi: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Caroline Louis-Brennetot: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Cécile Pierre-Eugène: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Margot Gautier: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Ana Costa: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Amandine Grelier: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Sakina Zaïdi: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Nadège Gruel: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Irène Jimenez: Adolescents and Young Adults with Cancer, Institut Curie
Eve Lapouble: Institut Curie, Unité de Génétique Somatique
Gaëlle Pierron: Institut Curie, Unité de Génétique Somatique
Déborah Sitbon: Institut Curie, Unité de Génétique Somatique
Hervé J. Brisse: PSL Research University
Arnaud Gauthier: Institut Curie, Department of Biopathology
Paul Fréneaux: Institut Curie, Department of Biopathology
Sandrine Grossetête: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Laura G. Baudrin: Paris, France. Institut Curie, Single Cell Initiative
Virginie Raynal: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Sylvain Baulande: Paris, France. Institut Curie, Single Cell Initiative
Angela Bellini: Adolescents and Young Adults with Cancer, Institut Curie
Jaydutt Bhalshankar: Adolescents and Young Adults with Cancer, Institut Curie
Angel M. Carcaboso: Institut de Recerca Sant Joan de Déu
Birgit Geoerger: Université Paris-Saclay
Hermann Rohrer: Goethe University
Didier Surdez: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Valentina Boeva: Paris University
Gudrun Schleiermacher: Adolescents and Young Adults with Cancer, Institut Curie
Olivier Delattre: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab
Isabelle Janoueix-Lerosey: PSL Research University, Diversity and Plasticity of Childhood Tumors Lab

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Noradrenergic 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.

Date: 2023
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DOI: 10.1038/s41467-023-38239-5

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