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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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 |
format | Article |
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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.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-019-52143-3</identifier><identifier>PMID: 31676869</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>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</subject><ispartof>Scientific reports, 2019-11, Vol.9 (1), p.15812-15812, Article 15812</ispartof><rights>The Author(s) 2019</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c451t-bb1e87c68a3ee04adc0c1877d4cc7bfb3415c67df1e6fa7ed413d2a1b448dfdb3</citedby><cites>FETCH-LOGICAL-c451t-bb1e87c68a3ee04adc0c1877d4cc7bfb3415c67df1e6fa7ed413d2a1b448dfdb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825133/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825133/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27922,27923,41118,42187,51574,53789,53791</link.rule.ids></links><search><creatorcontrib>Nakai, Sho</creatorcontrib><creatorcontrib>Yamada, Shutaro</creatorcontrib><creatorcontrib>Outani, Hidetatsu</creatorcontrib><creatorcontrib>Nakai, Takaaki</creatorcontrib><creatorcontrib>Yasuda, Naohiro</creatorcontrib><creatorcontrib>Mae, Hirokazu</creatorcontrib><creatorcontrib>Imura, Yoshinori</creatorcontrib><creatorcontrib>Wakamatsu, Toru</creatorcontrib><creatorcontrib>Tamiya, Hironari</creatorcontrib><creatorcontrib>Tanaka, Takaaki</creatorcontrib><creatorcontrib>Hamada, Kenichiro</creatorcontrib><creatorcontrib>Tani, Akiyoshi</creatorcontrib><creatorcontrib>Myoui, Akira</creatorcontrib><creatorcontrib>Araki, Nobuhito</creatorcontrib><creatorcontrib>Ueda, Takafumi</creatorcontrib><creatorcontrib>Yoshikawa, Hideki</creatorcontrib><creatorcontrib>Takenaka, Satoshi</creatorcontrib><creatorcontrib>Naka, Norifumi</creatorcontrib><title>Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><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.</description><subject>13/1</subject><subject>13/31</subject><subject>13/51</subject><subject>13/95</subject><subject>38/32</subject><subject>38/61</subject><subject>38/77</subject><subject>38/90</subject><subject>45/23</subject><subject>631/67/1059/602</subject><subject>631/67/1798</subject><subject>631/67/322</subject><subject>631/67/70</subject><subject>631/80/86/2368</subject><subject>64/60</subject><subject>82/80</subject><subject>AKT protein</subject><subject>Antineoplastic drugs</subject><subject>Antitumor agents</subject><subject>Autocrine signalling</subject><subject>Cell activation</subject><subject>Cell fusion</subject><subject>Chromosome rearrangements</subject><subject>Drug development</subject><subject>Drug screening</subject><subject>FLI-1 protein</subject><subject>Fusion protein</subject><subject>Humanities and Social Sciences</subject><subject>Insulin</subject><subject>Insulin-like growth factor I</subject><subject>Insulin-like growth factors</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>multidisciplinary</subject><subject>R&D</subject><subject>Research & development</subject><subject>Sarcoma</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signal transduction</subject><subject>Tumors</subject><subject>Xenografts</subject><subject>Young adults</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kctuFDEQRS0EIlHID7CyxIZFDF22-7VBQpMHIyIhJURiZ1W73dOOuu3Bdg_iH_hoPJmI1wJvbKlO3bquS8hLKN5AIZq3UULZNqyAlpUcpGDiCTnmhSwZF5w__eN9RE5jvC_yKXkroX1OjgRUddVU7TH5cRETdpON42xcon6gSJ3fmYmOy4yOrtYrdn73RdKIQfsZqTbTRCfrzBn9aFNAdntze0a_2TRSXJLXIZfo-uqSwQ1FnewOk_WOouvpbBLmaclquvUpj7M40eRpGg2dFreJL8izAadoTh_vE3J3efF59YFdf7par95fMy1LSKzrwDS1rhoUxhQSe11oaOq6l1rX3dCJvBpd1f0AphqwNr0E0XOETsqmH_pOnJB3B93t0s2m19lKwEltg50xfFcerfq74uyoNn6nqoaXIEQWeP0oEPzXxcSkZhv3m0Fn_BIVFwCVlEUFGX31D3rvl-Dy9x4ozqGteab4gdLBxxjM8MsMFGqftzrkrXLe6iFvtXchDk0xw25jwm_p_3T9BPnJraM</recordid><startdate>20191101</startdate><enddate>20191101</enddate><creator>Nakai, Sho</creator><creator>Yamada, Shutaro</creator><creator>Outani, Hidetatsu</creator><creator>Nakai, Takaaki</creator><creator>Yasuda, Naohiro</creator><creator>Mae, Hirokazu</creator><creator>Imura, Yoshinori</creator><creator>Wakamatsu, Toru</creator><creator>Tamiya, Hironari</creator><creator>Tanaka, Takaaki</creator><creator>Hamada, Kenichiro</creator><creator>Tani, Akiyoshi</creator><creator>Myoui, Akira</creator><creator>Araki, Nobuhito</creator><creator>Ueda, Takafumi</creator><creator>Yoshikawa, Hideki</creator><creator>Takenaka, Satoshi</creator><creator>Naka, Norifumi</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20191101</creationdate><title>Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c451t-bb1e87c68a3ee04adc0c1877d4cc7bfb3415c67df1e6fa7ed413d2a1b448dfdb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>13/1</topic><topic>13/31</topic><topic>13/51</topic><topic>13/95</topic><topic>38/32</topic><topic>38/61</topic><topic>38/77</topic><topic>38/90</topic><topic>45/23</topic><topic>631/67/1059/602</topic><topic>631/67/1798</topic><topic>631/67/322</topic><topic>631/67/70</topic><topic>631/80/86/2368</topic><topic>64/60</topic><topic>82/80</topic><topic>AKT protein</topic><topic>Antineoplastic drugs</topic><topic>Antitumor agents</topic><topic>Autocrine signalling</topic><topic>Cell activation</topic><topic>Cell fusion</topic><topic>Chromosome rearrangements</topic><topic>Drug development</topic><topic>Drug screening</topic><topic>FLI-1 protein</topic><topic>Fusion protein</topic><topic>Humanities and Social Sciences</topic><topic>Insulin</topic><topic>Insulin-like growth factor I</topic><topic>Insulin-like growth factors</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>multidisciplinary</topic><topic>R&D</topic><topic>Research & development</topic><topic>Sarcoma</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Signal transduction</topic><topic>Tumors</topic><topic>Xenografts</topic><topic>Young adults</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nakai, Sho</creatorcontrib><creatorcontrib>Yamada, Shutaro</creatorcontrib><creatorcontrib>Outani, 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nakai, Sho</au><au>Yamada, Shutaro</au><au>Outani, Hidetatsu</au><au>Nakai, Takaaki</au><au>Yasuda, Naohiro</au><au>Mae, Hirokazu</au><au>Imura, Yoshinori</au><au>Wakamatsu, Toru</au><au>Tamiya, Hironari</au><au>Tanaka, Takaaki</au><au>Hamada, Kenichiro</au><au>Tani, Akiyoshi</au><au>Myoui, Akira</au><au>Araki, Nobuhito</au><au>Ueda, Takafumi</au><au>Yoshikawa, Hideki</au><au>Takenaka, Satoshi</au><au>Naka, Norifumi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><date>2019-11-01</date><risdate>2019</risdate><volume>9</volume><issue>1</issue><spage>15812</spage><epage>15812</epage><pages>15812-15812</pages><artnum>15812</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>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.</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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source | DOAJ Directory of Open Access Journals; Springer Nature OA Free Journals; Nature Free; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
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 |