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

Gaylor Boulay, Liliane C. Broye, Rui Dong, Sowmya Iyer, Rajendran Sanalkumar, Yu-Hang Xing, Rémi Buisson, Shruthi Rengarajan, Beverly Naigles, Benoît Duc, Angela Volorio, Mary E. Awad, Raffaele Renella, Ivan Chebib, G. Petur Nielsen, Edwin Choy, Gregory M. Cote, Lee Zou, Igor Letovanec, Ivan Stamenkovic, Miguel N. Rivera () and Nicolò Riggi ()
Additional contact information
Gaylor Boulay: Massachusetts General Hospital and Harvard Medical School
Liliane C. Broye: Lausanne University Hospital & University of Lausanne
Rui Dong: Massachusetts General Hospital and Harvard Medical School
Sowmya Iyer: Massachusetts General Hospital and Harvard Medical School
Rajendran Sanalkumar: Lausanne University Hospital & University of Lausanne
Yu-Hang Xing: Massachusetts General Hospital and Harvard Medical School
Rémi Buisson: Massachusetts General Hospital and Harvard Medical School
Shruthi Rengarajan: Massachusetts General Hospital and Harvard Medical School
Beverly Naigles: Massachusetts General Hospital and Harvard Medical School
Benoît Duc: Lausanne University Hospital & University of Lausanne
Angela Volorio: Massachusetts General Hospital and Harvard Medical School
Mary E. Awad: Massachusetts General Hospital and Harvard Medical School
Raffaele Renella: Lausanne University Hospital and University of Lausanne
Ivan Chebib: Massachusetts General Hospital and Harvard Medical School
G. Petur Nielsen: Massachusetts General Hospital and Harvard Medical School
Edwin Choy: Massachusetts General Hospital
Gregory M. Cote: Massachusetts General Hospital
Lee Zou: Massachusetts General Hospital and Harvard Medical School
Igor Letovanec: Valais Hospital
Ivan Stamenkovic: Lausanne University Hospital & University of Lausanne
Miguel N. Rivera: Massachusetts General Hospital and Harvard Medical School
Nicolò Riggi: Lausanne University Hospital & University of Lausanne

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-51851-3

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