Dysregulated heparan sulfate proteoglycan metabolism promotes Ewing sarcoma tumor growth
The Ewing sarcoma family of tumors is a group of malignant small round blue cell tumors (SRBCTs) that affect children, adolescents, and young adults. The tumors are characterized by reciprocal chromosomal translocations that generate chimeric fusion oncogenes, the most common of which is EWSR1-FLI1....
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/69734 |
| _version_ | 1797991964481683456 |
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| author | Elena Vasileva Mikako Warren Timothy J Triche James F Amatruda |
| author_facet | Elena Vasileva Mikako Warren Timothy J Triche James F Amatruda |
| author_sort | Elena Vasileva |
| collection | DOAJ |
| description | The Ewing sarcoma family of tumors is a group of malignant small round blue cell tumors (SRBCTs) that affect children, adolescents, and young adults. The tumors are characterized by reciprocal chromosomal translocations that generate chimeric fusion oncogenes, the most common of which is EWSR1-FLI1. Survival is extremely poor for patients with metastatic or relapsed disease, and no molecularly targeted therapy for this disease currently exists. The absence of a reliable genetic animal model of Ewing sarcoma has impaired investigation of tumor cell/microenvironmental interactions in vivo. We have developed a new genetic model of Ewing sarcoma based on Cre-inducible expression of human EWSR1-FLI1 in wild-type zebrafish, which causes rapid onset of SRBCTs at high penetrance. The tumors express canonical EWSR1-FLI1 target genes and stain for known Ewing sarcoma markers including CD99. Growth of tumors is associated with activation of the MAPK/ERK pathway, which we link to dysregulated extracellular matrix metabolism in general and heparan sulfate proteoglycan catabolism in particular. Targeting heparan sulfate proteoglycans with the specific heparan sulfate antagonist Surfen reduces ERK1/2 signaling and decreases tumorigenicity of Ewing sarcoma cells in vitro and in vivo. These results highlight the important role of the extracellular matrix in Ewing sarcoma tumor growth and the potential of agents targeting proteoglycan metabolism as novel therapies for this disease. |
| first_indexed | 2024-04-11T08:59:24Z |
| format | Article |
| id | doaj.art-58e3b2f803f1456eb7be71c47f2d6662 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T08:59:24Z |
| publishDate | 2022-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-58e3b2f803f1456eb7be71c47f2d66622022-12-22T04:32:49ZengeLife Sciences Publications LtdeLife2050-084X2022-03-011110.7554/eLife.69734Dysregulated heparan sulfate proteoglycan metabolism promotes Ewing sarcoma tumor growthElena Vasileva0https://orcid.org/0000-0003-2026-1331Mikako Warren1Timothy J Triche2James F Amatruda3https://orcid.org/0000-0002-9901-2137Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, United StatesDivision of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, United States; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, United StatesDivision of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, United States; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, United StatesCancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, United States; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, United States; Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, United StatesThe Ewing sarcoma family of tumors is a group of malignant small round blue cell tumors (SRBCTs) that affect children, adolescents, and young adults. The tumors are characterized by reciprocal chromosomal translocations that generate chimeric fusion oncogenes, the most common of which is EWSR1-FLI1. Survival is extremely poor for patients with metastatic or relapsed disease, and no molecularly targeted therapy for this disease currently exists. The absence of a reliable genetic animal model of Ewing sarcoma has impaired investigation of tumor cell/microenvironmental interactions in vivo. We have developed a new genetic model of Ewing sarcoma based on Cre-inducible expression of human EWSR1-FLI1 in wild-type zebrafish, which causes rapid onset of SRBCTs at high penetrance. The tumors express canonical EWSR1-FLI1 target genes and stain for known Ewing sarcoma markers including CD99. Growth of tumors is associated with activation of the MAPK/ERK pathway, which we link to dysregulated extracellular matrix metabolism in general and heparan sulfate proteoglycan catabolism in particular. Targeting heparan sulfate proteoglycans with the specific heparan sulfate antagonist Surfen reduces ERK1/2 signaling and decreases tumorigenicity of Ewing sarcoma cells in vitro and in vivo. These results highlight the important role of the extracellular matrix in Ewing sarcoma tumor growth and the potential of agents targeting proteoglycan metabolism as novel therapies for this disease.https://elifesciences.org/articles/69734Ewing sarcomaproteoglycanscancerSurfenextracellular matrix |
| spellingShingle | Elena Vasileva Mikako Warren Timothy J Triche James F Amatruda Dysregulated heparan sulfate proteoglycan metabolism promotes Ewing sarcoma tumor growth eLife Ewing sarcoma proteoglycans cancer Surfen extracellular matrix |
| title | Dysregulated heparan sulfate proteoglycan metabolism promotes Ewing sarcoma tumor growth |
| title_full | Dysregulated heparan sulfate proteoglycan metabolism promotes Ewing sarcoma tumor growth |
| title_fullStr | Dysregulated heparan sulfate proteoglycan metabolism promotes Ewing sarcoma tumor growth |
| title_full_unstemmed | Dysregulated heparan sulfate proteoglycan metabolism promotes Ewing sarcoma tumor growth |
| title_short | Dysregulated heparan sulfate proteoglycan metabolism promotes Ewing sarcoma tumor growth |
| title_sort | dysregulated heparan sulfate proteoglycan metabolism promotes ewing sarcoma tumor growth |
| topic | Ewing sarcoma proteoglycans cancer Surfen extracellular matrix |
| url | https://elifesciences.org/articles/69734 |
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