LIN28B Underlies the Pathogenesis of a Subclass of Ewing Sarcoma LIN28B Control of EWS-FLI1 Stability

Tugba Keskin; Arnaud Bakaric; Patricia Waszyk; Gaylor Boulay; Matteo Torsello; Sandrine Cornaz-Buros; Nadja Chevalier; Thibaud Geiser; Patricia Martin; Angela Volorio; Sowmya Iyer; Anupriya Kulkarni; Igor Letovanec; Stéphane Cherix; Gregory M Cote; Edwin Choy; Antonia Digklia; Michael Montemurro; Ivan Chebib; Petur G Nielsen; Angel M Carcaboso; Jaume Mora; Raffaele Renella; Mario L Suvà; Carlo Fusco; Paolo Provero; Miguel N Rivera; Nicolò Riggi; Ivan Stamenkovic

doi:10.1016/j.celrep.2019.12.053

LIN28B Underlies the Pathogenesis of a Subclass of Ewing Sarcoma LIN28B Control of EWS-FLI1 Stability

Cell Rep. 2020 Mar 31;30(13):4567-4583.e5. doi: 10.1016/j.celrep.2019.12.053.

Authors

Tugba Keskin¹, Arnaud Bakaric¹, Patricia Waszyk¹, Gaylor Boulay², Matteo Torsello³, Sandrine Cornaz-Buros⁴, Nadja Chevalier⁵, Thibaud Geiser¹, Patricia Martin¹, Angela Volorio⁶, Sowmya Iyer⁷, Anupriya Kulkarni⁷, Igor Letovanec⁸, Stéphane Cherix⁹, Gregory M Cote¹⁰, Edwin Choy¹⁰, Antonia Digklia¹¹, Michael Montemurro¹¹, Ivan Chebib¹², Petur G Nielsen¹², Angel M Carcaboso¹³, Jaume Mora¹³, Raffaele Renella¹⁴, Mario L Suvà⁷, Carlo Fusco¹, Paolo Provero¹⁵, Miguel N Rivera², Nicolò Riggi¹, Ivan Stamenkovic¹⁶

Affiliations

¹ Experimental Pathology Service, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland.
² Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ Experimental Pathology Service, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland; Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland.
⁴ Experimental Pathology Service, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland; Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland.
⁵ Experimental Pathology Service, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland; Department Woman-Mother-Child, Division of Pediatrics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland.
⁶ Experimental Pathology Service, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁷ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁸ Department of Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland.
⁹ Department of Orthopaedics and Traumatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland.
¹⁰ Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹¹ Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland.
¹² Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹³ Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, 08950 Barcelona, Spain.
¹⁴ Department Woman-Mother-Child, Division of Pediatrics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland.
¹⁵ Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, 20132 Milan, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, 10124 Turin, Italy.
¹⁶ Experimental Pathology Service, Centre Hospitalier Universitaire Vaudois, University of Lausanne, 1011 Lausanne, Switzerland. Electronic address: ivan.stamenkovic@chuv.ch.

PMID: 32234488
DOI: 10.1016/j.celrep.2019.12.053

Abstract

Ewing sarcoma (EwS) is associated with poor prognosis despite current multimodal therapy. Targeting of EWS-FLI1, the fusion protein responsible for its pathogenesis, and its principal downstream targets has not yet produced satisfactory therapeutic options, fueling the search for alternative approaches. Here, we show that the oncofetal RNA-binding protein LIN28B regulates the stability of EWS-FLI1 mRNA in ~10% of EwSs. LIN28B depletion in these tumors leads to a decrease in the expression of EWS-FLI1 and its direct transcriptional network, abrogating EwS cell self-renewal and tumorigenicity. Moreover, pharmacological inhibition of LIN28B mimics the effect of LIN28B depletion, suggesting that LIN28B sustains the emergence of a subset of EwS in which it also serves as an effective therapeutic target.

Keywords: EWS-FLI-1 mRNA stabilization; Ewing sarcoma; Lin28B; poor prognosis; therapeutic target.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis / genetics
Carcinogenesis / pathology
Cell Line, Tumor
Cell Proliferation
Cell Self Renewal
Clone Cells
Gene Expression Regulation, Neoplastic
Humans
Kinetics
Mice
Oncogene Proteins, Fusion / metabolism*
Protein Stability
Proto-Oncogene Protein c-fli-1 / metabolism*
RNA Stability
RNA-Binding Protein EWS / metabolism*
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
Sarcoma, Ewing / genetics
Sarcoma, Ewing / pathology*
Spheroids, Cellular / pathology

Substances

EWS-FLI fusion protein
LIN28B protein, human
Oncogene Proteins, Fusion
Proto-Oncogene Protein c-fli-1
RNA-Binding Protein EWS
RNA-Binding Proteins