EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in desmoplastic small round cell tumors

• Published in: Nature communications Vol. 15; no. 1; pp. 7460 - 17
• Main Authors: Boulay, Gaylor, Broye, Liliane C., Dong, Rui, Iyer, Sowmya, Sanalkumar, Rajendran, Xing, Yu-Hang, Buisson, Rémi, Rengarajan, Shruthi, Naigles, Beverly, Duc, Benoît, Volorio, Angela, Awad, Mary E., Renella, Raffaele, Chebib, Ivan, Nielsen, G. Petur, Choy, Edwin, Cote, Gregory M., Zou, Lee, Letovanec, Igor, Stamenkovic, Ivan, Rivera, Miguel N., Riggi, Nicolò
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/89; 14/32; 38/15; 38/88; 38/91; 45/70; 631/1647/2210/2211; 631/337/572/2102; 631/67/1798; 631/80/304; Animals; Binding; Cell fusion; Cell Line, Tumor; Chromatin; Chromatin - metabolism; Cyclin D1 - genetics; Cyclin D1 - metabolism; Deoxyribonucleic acid; Desmoplastic Small Round Cell Tumor - drug therapy; Desmoplastic Small Round Cell Tumor - genetics; Desmoplastic Small Round Cell Tumor - metabolism; Desmoplastic Small Round Cell Tumor - pathology; DNA; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene regulation; Gene Regulatory Networks; Genes; Humanities and Social Sciences; Humans; In vivo methods and tests; Isoforms; Malignancy; Mice; multidisciplinary; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncoproteins; Piperazines - pharmacology; Protein Isoforms - genetics; Protein Isoforms - metabolism; Pyridines - pharmacology; RNA-Binding Protein EWS - genetics; RNA-Binding Protein EWS - metabolism; Science; Science (multidisciplinary); Tumors; WT1 Proteins - genetics; WT1 Proteins - metabolism; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51851-3

EWS fusion oncoproteins underlie several human malignancies including Desmoplastic Small Round Cell Tumor (DSRCT), an aggressive cancer driven by EWS-WT1 fusion proteins. Here we combine chromatin occupancy and 3D profiles to identify EWS-WT1-dependent gene regulation networks and target genes. We show that EWS-WT1 is a powerful chromatin activator controlling an oncogenic gene expression program that characterizes primary tumors. Similar to wild type WT1, EWS-WT1 has two isoforms that differ in their DNA binding domain and we find that they have distinct DNA binding profiles and are both required to generate viable tumors that resemble primary DSRCT. Finally, we identify candidate EWS-WT1 target genes with potential therapeutic implications, including CCND1 , whose inhibition by the clinically-approved drug Palbociclib leads to marked tumor burden decrease in DSRCT PDXs in vivo. Taken together, our studies identify gene regulation programs and therapeutic vulnerabilities in DSRCT and provide a mechanistic understanding of the complex oncogenic activity of EWS-WT1. Desmoplastic Small Round Cell Tumor (DSRCT) is an aggressive malignancy characterized by EWS-WT1 fusion oncoproteins with limited mechanistic understanding. Here, the authors identify EWS-WT1-dependent gene regulation networks and target genes, as well as the activities of two EWS-WT1 isoforms with distinct DNA binding profiles, both of which are indispensable for DSRCT formation.