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Therapeutic Potential of EWSR1–FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma

1
Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), 28220 Madrid, Spain
2
Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (CB06/07/1009; CIBERER-ISCIII), 28029 Madrid, Spain
3
Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Carretera de Colmenar km 9.100, 28034 Madrid, Spain
4
Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (CB06/07/0048; CIBERER-ISCIII), 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
Academic Editors: Torsten Kessler and Mary Frances McMullin
Cancers 2021, 13(15), 3783; https://doi.org/10.3390/cancers13153783
Received: 19 April 2021 / Revised: 13 July 2021 / Accepted: 23 July 2021 / Published: 27 July 2021
(This article belongs to the Section Cancer Therapy)
Ewing sarcoma is an aggressive tumor with still unacceptable survival rates, particularly in patients with metastatic disease and for which it is necessary to develop new and innovative therapies. These tumors are characterized by the presence of chromosomal translocations that give rise to chimeric transcription factors (i.e., EWSR1–FLI1) that govern the oncogenic process. In this article, we describe an efficient strategy to permanently inactivate the EWSR1–FLI1 oncogene characteristic of Ewing sarcoma using CRISPR/Cas9 gene editing technology. Although the application of gene therapy in cancer still has many limitations, for example, the strategy for delivery, studies like ours show that gene therapy can be a promising alternative, particularly for those tumors that are highly dependent on a particular oncogene as is the case in Ewing sarcoma.
Ewing sarcoma is an aggressive bone cancer affecting children and young adults. The main molecular hallmark of Ewing sarcoma are chromosomal translocations that produce chimeric oncogenic transcription factors, the most frequent of which is the aberrant transcription factor EWSR1–FLI1. Because this is the principal oncogenic driver of Ewing sarcoma, its inactivation should be the best therapeutic strategy to block tumor growth. In this study, we genetically inactivated EWSR1–FLI1 using CRISPR-Cas9 technology in order to cause permanent gene inactivation. We found that gene editing at the exon 9 of FLI1 was able to block cell proliferation drastically and induce senescence massively in the well-studied Ewing sarcoma cell line A673. In comparison with an extensively used cellular model of EWSR1–FLI1 knockdown (A673/TR/shEF), genetic inactivation was more effective, particularly in its capability to block cell proliferation. In summary, genetic inactivation of EWSR1–FLI1 in A673 Ewing sarcoma cells blocks cell proliferation and induces a senescence phenotype that could be exploited therapeutically. Although efficient and specific in vivo CRISPR-Cas9 editing still presents many challenges today, our data suggest that complete inactivation of EWSR1–FLI1 at the cell level should be considered a therapeutic approach to develop in the future. View Full-Text
Keywords: Ewing sarcoma; EWSR1–FLI1; CRISPR/Cas9; gene therapy; cell cycle arrest; senescence Ewing sarcoma; EWSR1–FLI1; CRISPR/Cas9; gene therapy; cell cycle arrest; senescence
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MDPI and ACS Style

Cervera, S.T.; Rodríguez-Martín, C.; Fernández-Tabanera, E.; Melero-Fernández de Mera, R.M.; Morin, M.; Fernández-Peñalver, S.; Iranzo-Martínez, M.; Amhih-Cardenas, J.; García-García, L.; González-González, L.; Moreno-Pelayo, M.A.; Alonso, J. Therapeutic Potential of EWSR1–FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma. Cancers 2021, 13, 3783. https://doi.org/10.3390/cancers13153783

AMA Style

Cervera ST, Rodríguez-Martín C, Fernández-Tabanera E, Melero-Fernández de Mera RM, Morin M, Fernández-Peñalver S, Iranzo-Martínez M, Amhih-Cardenas J, García-García L, González-González L, Moreno-Pelayo MA, Alonso J. Therapeutic Potential of EWSR1–FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma. Cancers. 2021; 13(15):3783. https://doi.org/10.3390/cancers13153783

Chicago/Turabian Style

Cervera, Saint T., Carlos Rodríguez-Martín, Enrique Fernández-Tabanera, Raquel M. Melero-Fernández de Mera, Matias Morin, Sergio Fernández-Peñalver, Maria Iranzo-Martínez, Jorge Amhih-Cardenas, Laura García-García, Laura González-González, Miguel Angel Moreno-Pelayo, and Javier Alonso. 2021. "Therapeutic Potential of EWSR1–FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma" Cancers 13, no. 15: 3783. https://doi.org/10.3390/cancers13153783

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