Neuroblastomas: an extremely diverse type of pediatric tumors
One tumor, but two tumor cell identities: that is the conclusion of the latest discoveries by one Institut Curie team specializing in pediatric cancers.
Every year, 130 to 150 children are diagnosed in France with a neuroblastoma. These tumors are characterized by extreme clinical variability and rapid changes: some regress spontaneously without treatment. Others evolve rapidly into a form that is often fatal, even when intensive chemotherapy initially produces a decrease or even disappearance of the clinical signs.
Our goal is to try to understand the wide variety of neuroblastomas by studying the biological characteristics of these pediatric tumors,” explains Isabelle Janoueix-Lerosey, PhD, Inserm research director on the Genetics and biology of pediatric tumors team (Inserm/Institut Curie).
The team has just reached a new phase in this effort by looking at cells taken from neuroblastomas from a different perspective.“Because these tumors develop from cells derived from the neural crest, i.e. embryonic cells, we took a look at how the expression of genes in these cells is set up,” explains Janoueix-Lerosey. The way genes are expressed defines a cell’s unique characteristics. Influenced by genes known as transcription factors, certain genes are turned on or off. Institut Curie researchers explored the network of transcription factors that control the expression of genes in neuroblastoma cells. Depending on which networks are involved, it appears that a tumor can develop two different cellular identities. The proportion of these two cellular identities varies from one neuroblastoma to another without appearing to influence their aggressiveness. On the other hand, interesting information emerges when you consider the effects of the chemotherapy commonly used to treat young patients. “In cellular models of neuroblastomas analyzed in vitro, we observed an increase in one of the cellular identities after treatment with chemotherapy molecules,” describes the researcher. This over-representation of one cellular identity is not observed in relapses of neuroblastoma. “This leads us to believe that the cells possess a certain plasticity, allowing them to switch from one identity to the other.” But that conclusion is only a new beginning: the team’s new aim is to find a molecule that attacks the cellular identity which appears to resist chemotherapy, or at least is over-represented after treatment. “To treat young patients and reduce the risk of relapse, we need to eradicate both types of cellular identity. But it seems that current chemotherapy eliminates only one of them, and we don’t yet really know why,” concludes Janoueix-Lerosey, who has already planned the next experiments to help address this double challenge.
Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries.
Valentina Boeva, Caroline Louis-Brennetot, Agathe Peltier, Simon Durand, Cécile Pierre-Eugène, Virginie Raynal, Heather C Etchevers, Sophie Thomas, Alban Lermine, Estelle Daudigeos-Dubus, Birgit Geoerger, Martin F Orth, Thomas G P Grünewald, Elise Diaz, Bertrand Ducos, Didier Surdez, Angel M Carcaboso, Irina Medvedeva, Thomas Deller, Valérie Combaret, Eve Lapouble, Gaelle Pierron, Sandrine Grossetête-Lalami, Sylvain Baulande, Gudrun Schleiermacher, Emmanuel Barillot, Hermann Rohrer, Olivier Delattre & Isabelle Janoueix-Lerosey
Nature Genetics, doi:10.1038/ng.3921, 24 juillet 2017
copyright : Christophe Hargouès/Institut Curie
