Two discoveries to better understand metastatic processes in Ewing sarcoma
Thanks to world-renowned expertise combined with cutting-edge technologies, scientists have managed to identify the functions and structure of the genome and of its environment. Published in Cancer Cell and Nucleic Acids Research, their results offer longer-term hope for new targeted therapies.
Ewing sarcoma is a rare bone tumor that affects mainly children and adolescents. It affects around 80 young patients each year in France. This disease has a strong metastatic potential (lung, bone, bone marrow) and when it metastasizes, the prognosis is poor.
Almost 85% of Ewing tumors are caused by a genetic alteration (translocation) occurring between chromosomes 11 and 22, causing synthesis of an abnormal protein: EWS-FLI1. Its presence disrupts the functioning of thousands of genes: consequently cancer cells proliferate excessively but also migrate from their original site.
Institut Curie is a reference center for Ewing sarcoma treatment and has long-lasting experience in cancer research. Today, researchers from the SIREDO center (Care, Innovation & Research in Childhood, Adolescent and Young-Adult Oncology) at Institut Curie have just revealed two critical aspects linked to the aggressiveness of this tumor which could, in the coming years, lead to new therapeutic approaches.
STAG2 mutation conducts to altereted 3D structure of DNA
In Ewing sarcomas, the second most frequently mutation occurs in the STAG2 gene. This gene encodes for a component of a ring that allows DNA/chromatin loops to form. This three-dimensional structure of chromatin is essential for the structure of the genome and allows for proper gene activation and regulation. Researchers from Institut Curie have now shown that when STAG2 is mutated in Ewing sarcoma, the formation of these DNA loops is altered. This epigenetic disruption leads to an alteration of the activity of the EWS-FLI1 oncogene and lead to increased metastatic properties of the cancer cells.
Splicing defects involved in migration of tumors cell
In collaboration with a team from the University of Liège in Belgium, Institut Curie researchers looked at another biological process, namely splicing, which refers to the alterations that occur in the messenger RNA and that is critical to the good structure of proteins. They showed that the EWS-FLI1 protein which is specifically expressed in Ewing sarcoma, leads to splicing (a key process involved in mRNA maturation) alterations of genes that are involved for instance in cell migration, a major step in the formation of metastases.
Olivier Delattre, director of SIREDO at Institut Curie :
This long-haul work has revealed mechanisms that were unknown until now, specific to Ewing sarcoma. It highlights the processes triggered by mutations that encourage formation of metastases. We now need to continue this work to focus on new therapeutic approaches to target and counteract these malfunctions, and ultimately, achieve clinical applications for our young patients
STAG2 protein indirectly favors interactions between genes and other regions (called enhancer) present in these loops that fine tune gene regulatation. The loss of STAG2 following its mutation leads to a decrease in these interactions, causing deregulation of genes that favors metastatic processes.
> STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma. Didier Surdez, Sakina Zaidi, Sandrine Grossetête, Karine Laud-Duval, Anna Sole Ferre, Lieke Mous, Thomas Vourc'h, Franck Tirode, Gaelle Pierron, Virginie Raynal, Sylvain Baulande, Erika Brunet, Véronique Hill, Olivier Delattre. Cancer Cell, 2021. Read more
> ERG transcription factors have a splicing regulatory function involving RBFOX2 that is altered in the EWS-FLI1 oncogenic fusion. Olivier Saulnier, Katia Guedri-Idjouadiene, Marie-Ming Aynaud, Alina Chakraborty, Jonathan Bruyr, Joséphine Pineau, Tina O’Grady, Olivier Mirabeau, Sandrine Grossetête, Bartimée Galvan, Margaux Claes, Zahra Al Oula Hassoun, Benjamin Sadacca, Karine Laud, Sakina Zaïdi, Didier Surdez, Sylvain Baulande, Xavier Rambout, Franck Tirode, Martin Dutertre, Olivier Delattre, Franck Dequiedt, Nucleic Acids Research, 2021. Read more