Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs

Approximately 60–70% of EWSR1 -negative small blue round cell sarcomas harbour a rearrangement of CIC , most commonly CIC-DUX4 . CIC-DUX4 sarcoma (CDS) is an aggressive and often fatal high-grade sarcoma appearing predominantly in children and young adults. Although cell lines and their xenograft mo...

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Veröffentlicht in:Scientific reports 2019-11, Vol.9 (1), p.15812-15812, Article 15812
Hauptverfasser: Nakai, Sho, Yamada, Shutaro, Outani, Hidetatsu, Nakai, Takaaki, Yasuda, Naohiro, Mae, Hirokazu, Imura, Yoshinori, Wakamatsu, Toru, Tamiya, Hironari, Tanaka, Takaaki, Hamada, Kenichiro, Tani, Akiyoshi, Myoui, Akira, Araki, Nobuhito, Ueda, Takafumi, Yoshikawa, Hideki, Takenaka, Satoshi, Naka, Norifumi
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container_end_page 15812
container_issue 1
container_start_page 15812
container_title Scientific reports
container_volume 9
creator Nakai, Sho
Yamada, Shutaro
Outani, Hidetatsu
Nakai, Takaaki
Yasuda, Naohiro
Mae, Hirokazu
Imura, Yoshinori
Wakamatsu, Toru
Tamiya, Hironari
Tanaka, Takaaki
Hamada, Kenichiro
Tani, Akiyoshi
Myoui, Akira
Araki, Nobuhito
Ueda, Takafumi
Yoshikawa, Hideki
Takenaka, Satoshi
Naka, Norifumi
description Approximately 60–70% of EWSR1 -negative small blue round cell sarcomas harbour a rearrangement of CIC , most commonly CIC-DUX4 . CIC-DUX4 sarcoma (CDS) is an aggressive and often fatal high-grade sarcoma appearing predominantly in children and young adults. Although cell lines and their xenograft models are essential tools for basic research and development of antitumour drugs, few cell lines currently exist for CDS. We successfully established a novel human CDS cell line designated Kitra-SRS and developed orthotopic tumour xenografts in nude mice. The CIC-DUX4 fusion gene in Kitra-SRS cells was generated by t(12;19) complex chromosomal rearrangements with an insertion of a chromosome segment including a DUX4 pseudogene component. Kitra-SRS xenografts were histologically similar to the original tumour and exhibited metastatic potential to the lungs. Kitra-SRS cells displayed autocrine activation of the insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) pathway. Accordingly, treatment with the IGF-1R inhibitor, linsitinib, attenuated Kitra-SRS cell growth and IGF-1-induced activation of IGF-1R/AKT signalling both in vitro and in vivo . Furthermore, upon screening 1134 FDA-approved drugs, the responses of Kitra-SRS cells to anticancer drugs appeared to reflect those of the primary tumour. Our model will be a useful modality for investigating the molecular pathology and therapy of CDS.
doi_str_mv 10.1038/s41598-019-52143-3
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CIC-DUX4 sarcoma (CDS) is an aggressive and often fatal high-grade sarcoma appearing predominantly in children and young adults. Although cell lines and their xenograft models are essential tools for basic research and development of antitumour drugs, few cell lines currently exist for CDS. We successfully established a novel human CDS cell line designated Kitra-SRS and developed orthotopic tumour xenografts in nude mice. The CIC-DUX4 fusion gene in Kitra-SRS cells was generated by t(12;19) complex chromosomal rearrangements with an insertion of a chromosome segment including a DUX4 pseudogene component. Kitra-SRS xenografts were histologically similar to the original tumour and exhibited metastatic potential to the lungs. Kitra-SRS cells displayed autocrine activation of the insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) pathway. Accordingly, treatment with the IGF-1R inhibitor, linsitinib, attenuated Kitra-SRS cell growth and IGF-1-induced activation of IGF-1R/AKT signalling both in vitro and in vivo . Furthermore, upon screening 1134 FDA-approved drugs, the responses of Kitra-SRS cells to anticancer drugs appeared to reflect those of the primary tumour. 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CIC-DUX4 sarcoma (CDS) is an aggressive and often fatal high-grade sarcoma appearing predominantly in children and young adults. Although cell lines and their xenograft models are essential tools for basic research and development of antitumour drugs, few cell lines currently exist for CDS. We successfully established a novel human CDS cell line designated Kitra-SRS and developed orthotopic tumour xenografts in nude mice. The CIC-DUX4 fusion gene in Kitra-SRS cells was generated by t(12;19) complex chromosomal rearrangements with an insertion of a chromosome segment including a DUX4 pseudogene component. Kitra-SRS xenografts were histologically similar to the original tumour and exhibited metastatic potential to the lungs. Kitra-SRS cells displayed autocrine activation of the insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) pathway. Accordingly, treatment with the IGF-1R inhibitor, linsitinib, attenuated Kitra-SRS cell growth and IGF-1-induced activation of IGF-1R/AKT signalling both in vitro and in vivo . Furthermore, upon screening 1134 FDA-approved drugs, the responses of Kitra-SRS cells to anticancer drugs appeared to reflect those of the primary tumour. Our model will be a useful modality for investigating the molecular pathology and therapy of CDS.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31676869</pmid><doi>10.1038/s41598-019-52143-3</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record>
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subjects 13/1
13/31
13/51
13/95
38/32
38/61
38/77
38/90
45/23
631/67/1059/602
631/67/1798
631/67/322
631/67/70
631/80/86/2368
64/60
82/80
AKT protein
Antineoplastic drugs
Antitumor agents
Autocrine signalling
Cell activation
Cell fusion
Chromosome rearrangements
Drug development
Drug screening
FLI-1 protein
Fusion protein
Humanities and Social Sciences
Insulin
Insulin-like growth factor I
Insulin-like growth factors
Metastases
Metastasis
multidisciplinary
R&D
Research & development
Sarcoma
Science
Science (multidisciplinary)
Signal transduction
Tumors
Xenografts
Young adults
title Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-14T10%3A24%3A52IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Establishment%20of%20a%20novel%20human%20CIC-DUX4%20sarcoma%20cell%20line,%20Kitra-SRS,%20with%20autocrine%20IGF-1R%20activation%20and%20metastatic%20potential%20to%20the%20lungs&rft.jtitle=Scientific%20reports&rft.au=Nakai,%20Sho&rft.date=2019-11-01&rft.volume=9&rft.issue=1&rft.spage=15812&rft.epage=15812&rft.pages=15812-15812&rft.artnum=15812&rft.issn=2045-2322&rft.eissn=2045-2322&rft_id=info:doi/10.1038/s41598-019-52143-3&rft_dat=%3Cproquest_pubme%3E2311644061%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2311221972&rft_id=info:pmid/31676869&rfr_iscdi=true