EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma

Emely Möller, Viviane Praz, Sanalkumar Rajendran, Rui Dong, Alexandra Cauderay, Yu-Hang Xing, Lukuo Lee, Carlo Fusco, Liliane C. Broye, Luisa Cironi, Sowmya Iyer, Shruthi Rengarajan, Mary E. Awad, Beverly Naigles, Igor Letovanec, Nicola Ormas, Giovanna Finzi, Stefano Rosa, Fausto Sessa, Ivan Chebib, G. Petur Nielsen, Antonia Digklia, Dimitrios Spentzos, Gregory M. Cote, Edwin Choy, Martin Aryee, Ivan Stamenkovic, Gaylor Boulay, Miguel N. Rivera and Nicolò Riggi ()
Additional contact information
Emely Möller: Lausanne University Hospital and University of Lausanne
Viviane Praz: Lausanne University Hospital and University of Lausanne
Sanalkumar Rajendran: Lausanne University Hospital and University of Lausanne
Rui Dong: Massachusetts General Hospital
Alexandra Cauderay: Lausanne University Hospital and University of Lausanne
Yu-Hang Xing: Massachusetts General Hospital
Lukuo Lee: Massachusetts General Hospital
Carlo Fusco: Lausanne University Hospital and University of Lausanne
Liliane C. Broye: Lausanne University Hospital and University of Lausanne
Luisa Cironi: Lausanne University Hospital and University of Lausanne
Sowmya Iyer: Massachusetts General Hospital
Shruthi Rengarajan: Massachusetts General Hospital
Mary E. Awad: Massachusetts General Hospital
Beverly Naigles: Massachusetts General Hospital
Igor Letovanec: Central Institute, Valais Hospital
Nicola Ormas: ASST Sette Laghi
Giovanna Finzi: ASST Sette Laghi
Stefano Rosa: Lausanne University Hospital and University of Lausanne
Fausto Sessa: University of Insubria
Ivan Chebib: Massachusetts General Hospital and Harvard Medical School
G. Petur Nielsen: Massachusetts General Hospital and Harvard Medical School
Antonia Digklia: Lausanne University Hospital and University of Lausanne
Dimitrios Spentzos: Massachusetts General Hospital
Gregory M. Cote: Division of Hematology and Oncology, Massachusetts General Hospital
Edwin Choy: Division of Hematology and Oncology, Massachusetts General Hospital
Martin Aryee: Massachusetts General Hospital
Ivan Stamenkovic: Lausanne University Hospital and University of Lausanne
Gaylor Boulay: Massachusetts General Hospital
Miguel N. Rivera: Massachusetts General Hospital
Nicolò Riggi: Lausanne University Hospital and University of Lausanne

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.

Date: 2022
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DOI: 10.1038/s41467-022-29910-4

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