Super enhancers are strong spatiotemporal transcriptional regulators. They can be mapped on genomes thanks to their astounding enrichment for well-known enhancers markers, such as acetylation of the lysine 27 of type 3 histones (H3K27Ac). Their target genes, confined in their so-called topologically associated domains, present exceptionally high expression levels, depending on associated super enhancers activation status, and are responsible for defining cells identity whether physiological or pathological. Osteosarcomas are the most common primary malignant bone tumors. Patients suffering from osteosarcomas, on average 15 years old, mostly develop pulmonary metastasis, responsible for drastic decrease in their survival. We have conducted chromatin immunoprecipitation sequencing against H3K27Ac and RNA sequencing experiments on osteosarcoma cells presenting high propensity to metastatic dissemination or devoid of this capacity, in order to unveil genes implicated in metastasis development through super enhancers genomic mapping. We have highlighted exclusive active super enhancers profiles between metastatic and non-metastatic osteosarcoma cells. Among target genes of spotted super enhancers, three of them caught our attention. Implication of these genes in metastatic development have already been demonstrated in various cancers evolution, except in osteosarcomas. Osteosarcoma cells having high capacity for metastatic development present identified genes over expressions compared to cells incompetent in this pathological process. Artificial down expressions of identified genes decrease osteosarcoma cells metastatic capacity in vitro. In vivo experiments, that correspond to paratibial implantation of modified osteosarcoma cells and analysis of primary tumor metastatic development, are currently under way. Our strategy may allow identification of new therapeutic targets to fight against osteosarcoma metastatic evolution and open new perspectives to improve patients prognostic.
This work is funded by Ligue contre le cancer, ANR, SFCE and Région Pays de la Loire.
Citation Format: Mélanie Lavaud, Robel Tesfaye, Céline Charrier, Rose Anne Thépault, Maxime Golias, Sarah Le Page, Mathilde Mullard, Bénédicte Brounais, Franck Verrecchia, Marc Baud'huin, François Lamoureux, Steven Georges, Benjamin Ory. Identification of genes responsible for osteosarcomas metastatic evolution by active super enhancers profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6325.
