Dissecting genetic and microenvironmental determinants of aggressive cell state in synovial sarcoma

Livnat Jerby-Arnon†, Cyril Neftel†, Marni E. Shore, Matthew J. McBride, Brian Haas, Benjamin Izar, Angela Volorio, Gaylor Boulay, Luisa Cironi, Alyssa R. Richman, Liliane C. Broye, Joseph M. Gurski, Christina C. Luo, Ravindra Mylvaganam, Lan Nguyen, Shaolin Mei, Johannes c. Melms, Christophe Georgescu, Ofir Cohen, Jorge Buendia, Michael S. Cuoco, G. Petur Nielsen, Ivan Chebib, Gregory Cote, Edwin Choy, Igor Letovanec, Stéphane Cherix, Nikhil Wagle, Peter K. Sorger, Alex B. Haynes, John T. Mullen, Ivan Stamenkovic, Miguel N. Rivera, Cigall Kadoch, Orit Rozenblatt-Rosen, Mario L. Suvà‡, Nicolò Riggi‡, Aviv Regev‡

†these authors contributed equally to this work

‡these authors jointly supervised this work

The genetic, epigenetic and microenvironmental cues that shape the development and evolution of synovial sarcoma are only partly understood. Here, we leverage single cell RNA-Seq of 12 clinical tumor samples to identify the determinants of intra- and inter-tumor heterogeneity in synovial sarcoma. Tumors contain a subpopulation of malignant cells expressing a core oncogenic program of oxidative metabolism and immune evasion, which is predictive of metastatic disease and poor clinical outcomes. The program is positively regulated by the synovial sarcoma genetic driver and repressed by tumor microenvironment cytokines. We blocked the program by combining HDAC and CDK4/6 inhibitors as predicted by its features, selectively targeting synovial sarcoma cells, while sparing nonmalignant ones. Our study reveals unappreciated determinants of aggressiveness and suggests a novel combinatorial therapeutic strategy.