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The Transcriptional Coactivator TAZ Is a Potent Mediator of Alveolar Rhabdomyosarcoma Tumorigenesis
Alveolar rhabdomyosarcoma (aRMS) is a childhood soft tissue sarcoma driven by the signature (P3F) fusion gene. Five-year survival for aRMS is
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| Published in: | Clinical cancer research 2018-06, Vol.24 (11), p.2616-2630 |
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| container_title | Clinical cancer research |
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| creator | Deel, Michael D Slemmons, Katherine K Hinson, Ashley R Genadry, Katia C Burgess, Breanne A Crose, Lisa E S Kuprasertkul, Nina Oristian, Kristianne M Bentley, Rex C Linardic, Corinne M |
| description | Alveolar rhabdomyosarcoma (aRMS) is a childhood soft tissue sarcoma driven by the signature
(P3F) fusion gene. Five-year survival for aRMS is |
| doi_str_mv | 10.1158/1078-0432.CCR-17-1207 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2047595461</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2047595461</sourcerecordid><originalsourceid>FETCH-LOGICAL-c384t-a85562e2ef97341a31cac2b6547aaf4508c43e8126ad67c42efe2c6d706243113</originalsourceid><addsrcrecordid>eNo9kNtKxDAQhoMorq4-ghLwuprJoeleLsUTrChSb7wJs2mqXdpmTdoF397W09UMzPf_MB8hZ8AuAVR2BUxnCZOCX-b5cwI6Ac70HjkCpXQieKr2x_2PmZHjGDeMgQQmD8mMLxTITLIjYot3R4uAXbSh3va177ChuUfb1zvsfaDF8pXeR4r0yfeu6-mDK-vvg6_ostk532Cgz--4Ln376SMG61ukxdD6UL-5zsU6npCDCpvoTn_nnLzcXBf5XbJ6vL3Pl6vEikz2CWZKpdxxVy20kIACLFq-TpXUiJVULLNSuAx4imWqrRxBx21aapZyKQDEnFz89G6D_xhc7M3GD2F8KBrOpFYLJdOJUj-UDT7G4CqzDXWL4dMAM5NaM2kzkzYzqjWgzaR2zJ3_tg_r1pX_qT-X4gtFD3SN</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2047595461</pqid></control><display><type>article</type><title>The Transcriptional Coactivator TAZ Is a Potent Mediator of Alveolar Rhabdomyosarcoma Tumorigenesis</title><source>Science Journals (Open access)</source><creator>Deel, Michael D ; Slemmons, Katherine K ; Hinson, Ashley R ; Genadry, Katia C ; Burgess, Breanne A ; Crose, Lisa E S ; Kuprasertkul, Nina ; Oristian, Kristianne M ; Bentley, Rex C ; Linardic, Corinne M</creator><creatorcontrib>Deel, Michael D ; Slemmons, Katherine K ; Hinson, Ashley R ; Genadry, Katia C ; Burgess, Breanne A ; Crose, Lisa E S ; Kuprasertkul, Nina ; Oristian, Kristianne M ; Bentley, Rex C ; Linardic, Corinne M</creatorcontrib><description>Alveolar rhabdomyosarcoma (aRMS) is a childhood soft tissue sarcoma driven by the signature
(P3F) fusion gene. Five-year survival for aRMS is <50%, with no improvement in over 4 decades. Although the transcriptional coactivator TAZ is oncogenic in carcinomas, the role of TAZ in sarcomas is poorly understood. The aim of this study was to investigate the role of TAZ in P3F-aRMS tumorigenesis.
After determining from publicly available datasets that TAZ is upregulated in human aRMS transcriptomes, we evaluated whether TAZ is also upregulated in our myoblast-based model of P3F-initiated tumorigenesis, and performed IHC staining of 63 human aRMS samples from tissue microarrays. Using constitutive and inducible RNAi, we examined the impact of TAZ loss of function on aRMS oncogenic phenotypes
and tumorigenesis
Finally, we performed pharmacologic studies in aRMS cell lines using porphyrin compounds, which interfere with TAZ-TEAD transcriptional activity.
TAZ is upregulated in our P3F-initiated aRMS model, and aRMS cells and tumors have high nuclear TAZ expression.
, TAZ suppression inhibits aRMS cell proliferation, induces apoptosis, supports myogenic differentiation, and reduces aRMS cell stemness. TAZ-deficient aRMS cells are enriched in G
-M phase of the cell cycle.
, TAZ suppression attenuates aRMS xenograft tumor growth. Preclinical studies show decreased aRMS xenograft tumor growth with porphyrin compounds alone and in combination with vincristine.
TAZ is oncogenic in aRMS sarcomagenesis. While P3F is currently not therapeutically tractable, targeting TAZ could be a promising novel approach in aRMS.
.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-17-1207</identifier><identifier>PMID: 29514840</identifier><language>eng</language><publisher>United States: American Association for Cancer Research Inc</publisher><subject>Alveoli ; Animals ; Apoptosis ; Apoptosis - genetics ; Carcinoma ; Cell cycle ; Cell Cycle - genetics ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic - genetics ; Cell Transformation, Neoplastic - metabolism ; Children ; Disease Models, Animal ; DNA microarrays ; Experimental design ; Forkhead Box Protein O1 - genetics ; Forkhead Box Protein O1 - metabolism ; FOXO1 protein ; Fusion protein ; Gene Expression Regulation, Neoplastic ; Heterografts ; Humans ; In vivo methods and tests ; Mice ; Myoblasts - metabolism ; Pax3 protein ; PAX3 Transcription Factor - genetics ; PAX3 Transcription Factor - metabolism ; Pharmacology ; Phenotypes ; Rhabdomyosarcoma ; Rhabdomyosarcoma, Alveolar - genetics ; Rhabdomyosarcoma, Alveolar - metabolism ; RNA-mediated interference ; Sarcoma ; Soft tissue sarcoma ; Trans-Activators ; Transcription ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transcriptional Activation ; Tumorigenesis ; Tumors ; Vincristine ; Xenografts ; Xenotransplantation</subject><ispartof>Clinical cancer research, 2018-06, Vol.24 (11), p.2616-2630</ispartof><rights>2018 American Association for Cancer Research.</rights><rights>Copyright American Association for Cancer Research Inc Jun 1, 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c384t-a85562e2ef97341a31cac2b6547aaf4508c43e8126ad67c42efe2c6d706243113</citedby><cites>FETCH-LOGICAL-c384t-a85562e2ef97341a31cac2b6547aaf4508c43e8126ad67c42efe2c6d706243113</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29514840$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Deel, Michael D</creatorcontrib><creatorcontrib>Slemmons, Katherine K</creatorcontrib><creatorcontrib>Hinson, Ashley R</creatorcontrib><creatorcontrib>Genadry, Katia C</creatorcontrib><creatorcontrib>Burgess, Breanne A</creatorcontrib><creatorcontrib>Crose, Lisa E S</creatorcontrib><creatorcontrib>Kuprasertkul, Nina</creatorcontrib><creatorcontrib>Oristian, Kristianne M</creatorcontrib><creatorcontrib>Bentley, Rex C</creatorcontrib><creatorcontrib>Linardic, Corinne M</creatorcontrib><title>The Transcriptional Coactivator TAZ Is a Potent Mediator of Alveolar Rhabdomyosarcoma Tumorigenesis</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Alveolar rhabdomyosarcoma (aRMS) is a childhood soft tissue sarcoma driven by the signature
(P3F) fusion gene. Five-year survival for aRMS is <50%, with no improvement in over 4 decades. Although the transcriptional coactivator TAZ is oncogenic in carcinomas, the role of TAZ in sarcomas is poorly understood. The aim of this study was to investigate the role of TAZ in P3F-aRMS tumorigenesis.
After determining from publicly available datasets that TAZ is upregulated in human aRMS transcriptomes, we evaluated whether TAZ is also upregulated in our myoblast-based model of P3F-initiated tumorigenesis, and performed IHC staining of 63 human aRMS samples from tissue microarrays. Using constitutive and inducible RNAi, we examined the impact of TAZ loss of function on aRMS oncogenic phenotypes
and tumorigenesis
Finally, we performed pharmacologic studies in aRMS cell lines using porphyrin compounds, which interfere with TAZ-TEAD transcriptional activity.
TAZ is upregulated in our P3F-initiated aRMS model, and aRMS cells and tumors have high nuclear TAZ expression.
, TAZ suppression inhibits aRMS cell proliferation, induces apoptosis, supports myogenic differentiation, and reduces aRMS cell stemness. TAZ-deficient aRMS cells are enriched in G
-M phase of the cell cycle.
, TAZ suppression attenuates aRMS xenograft tumor growth. Preclinical studies show decreased aRMS xenograft tumor growth with porphyrin compounds alone and in combination with vincristine.
TAZ is oncogenic in aRMS sarcomagenesis. While P3F is currently not therapeutically tractable, targeting TAZ could be a promising novel approach in aRMS.
.</description><subject>Alveoli</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - genetics</subject><subject>Carcinoma</subject><subject>Cell cycle</subject><subject>Cell Cycle - genetics</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Children</subject><subject>Disease Models, Animal</subject><subject>DNA microarrays</subject><subject>Experimental design</subject><subject>Forkhead Box Protein O1 - genetics</subject><subject>Forkhead Box Protein O1 - metabolism</subject><subject>FOXO1 protein</subject><subject>Fusion protein</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Heterografts</subject><subject>Humans</subject><subject>In vivo methods and tests</subject><subject>Mice</subject><subject>Myoblasts - metabolism</subject><subject>Pax3 protein</subject><subject>PAX3 Transcription Factor - genetics</subject><subject>PAX3 Transcription Factor - metabolism</subject><subject>Pharmacology</subject><subject>Phenotypes</subject><subject>Rhabdomyosarcoma</subject><subject>Rhabdomyosarcoma, Alveolar - genetics</subject><subject>Rhabdomyosarcoma, Alveolar - metabolism</subject><subject>RNA-mediated interference</subject><subject>Sarcoma</subject><subject>Soft tissue sarcoma</subject><subject>Trans-Activators</subject><subject>Transcription</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transcriptional Activation</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Vincristine</subject><subject>Xenografts</subject><subject>Xenotransplantation</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNo9kNtKxDAQhoMorq4-ghLwuprJoeleLsUTrChSb7wJs2mqXdpmTdoF397W09UMzPf_MB8hZ8AuAVR2BUxnCZOCX-b5cwI6Ac70HjkCpXQieKr2x_2PmZHjGDeMgQQmD8mMLxTITLIjYot3R4uAXbSh3va177ChuUfb1zvsfaDF8pXeR4r0yfeu6-mDK-vvg6_ostk532Cgz--4Ln376SMG61ukxdD6UL-5zsU6npCDCpvoTn_nnLzcXBf5XbJ6vL3Pl6vEikz2CWZKpdxxVy20kIACLFq-TpXUiJVULLNSuAx4imWqrRxBx21aapZyKQDEnFz89G6D_xhc7M3GD2F8KBrOpFYLJdOJUj-UDT7G4CqzDXWL4dMAM5NaM2kzkzYzqjWgzaR2zJ3_tg_r1pX_qT-X4gtFD3SN</recordid><startdate>20180601</startdate><enddate>20180601</enddate><creator>Deel, Michael D</creator><creator>Slemmons, Katherine K</creator><creator>Hinson, Ashley R</creator><creator>Genadry, Katia C</creator><creator>Burgess, Breanne A</creator><creator>Crose, Lisa E S</creator><creator>Kuprasertkul, Nina</creator><creator>Oristian, Kristianne M</creator><creator>Bentley, Rex C</creator><creator>Linardic, Corinne M</creator><general>American Association for Cancer Research Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T5</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>20180601</creationdate><title>The Transcriptional Coactivator TAZ Is a Potent Mediator of Alveolar Rhabdomyosarcoma Tumorigenesis</title><author>Deel, Michael D ; Slemmons, Katherine K ; Hinson, Ashley R ; Genadry, Katia C ; Burgess, Breanne A ; Crose, Lisa E S ; Kuprasertkul, Nina ; Oristian, Kristianne M ; Bentley, Rex C ; Linardic, Corinne M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c384t-a85562e2ef97341a31cac2b6547aaf4508c43e8126ad67c42efe2c6d706243113</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Alveoli</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - genetics</topic><topic>Carcinoma</topic><topic>Cell cycle</topic><topic>Cell Cycle - genetics</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Cell Transformation, Neoplastic - genetics</topic><topic>Cell Transformation, Neoplastic - metabolism</topic><topic>Children</topic><topic>Disease Models, Animal</topic><topic>DNA microarrays</topic><topic>Experimental design</topic><topic>Forkhead Box Protein O1 - genetics</topic><topic>Forkhead Box Protein O1 - metabolism</topic><topic>FOXO1 protein</topic><topic>Fusion protein</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Heterografts</topic><topic>Humans</topic><topic>In vivo methods and tests</topic><topic>Mice</topic><topic>Myoblasts - metabolism</topic><topic>Pax3 protein</topic><topic>PAX3 Transcription Factor - genetics</topic><topic>PAX3 Transcription Factor - metabolism</topic><topic>Pharmacology</topic><topic>Phenotypes</topic><topic>Rhabdomyosarcoma</topic><topic>Rhabdomyosarcoma, Alveolar - genetics</topic><topic>Rhabdomyosarcoma, Alveolar - metabolism</topic><topic>RNA-mediated interference</topic><topic>Sarcoma</topic><topic>Soft tissue sarcoma</topic><topic>Trans-Activators</topic><topic>Transcription</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transcriptional Activation</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><topic>Vincristine</topic><topic>Xenografts</topic><topic>Xenotransplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Deel, Michael D</creatorcontrib><creatorcontrib>Slemmons, Katherine K</creatorcontrib><creatorcontrib>Hinson, Ashley R</creatorcontrib><creatorcontrib>Genadry, Katia C</creatorcontrib><creatorcontrib>Burgess, Breanne A</creatorcontrib><creatorcontrib>Crose, Lisa E S</creatorcontrib><creatorcontrib>Kuprasertkul, Nina</creatorcontrib><creatorcontrib>Oristian, Kristianne M</creatorcontrib><creatorcontrib>Bentley, Rex C</creatorcontrib><creatorcontrib>Linardic, Corinne M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Deel, Michael D</au><au>Slemmons, Katherine K</au><au>Hinson, Ashley R</au><au>Genadry, Katia C</au><au>Burgess, Breanne A</au><au>Crose, Lisa E S</au><au>Kuprasertkul, Nina</au><au>Oristian, Kristianne M</au><au>Bentley, Rex C</au><au>Linardic, Corinne M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Transcriptional Coactivator TAZ Is a Potent Mediator of Alveolar Rhabdomyosarcoma Tumorigenesis</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2018-06-01</date><risdate>2018</risdate><volume>24</volume><issue>11</issue><spage>2616</spage><epage>2630</epage><pages>2616-2630</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Alveolar rhabdomyosarcoma (aRMS) is a childhood soft tissue sarcoma driven by the signature
(P3F) fusion gene. Five-year survival for aRMS is <50%, with no improvement in over 4 decades. Although the transcriptional coactivator TAZ is oncogenic in carcinomas, the role of TAZ in sarcomas is poorly understood. The aim of this study was to investigate the role of TAZ in P3F-aRMS tumorigenesis.
After determining from publicly available datasets that TAZ is upregulated in human aRMS transcriptomes, we evaluated whether TAZ is also upregulated in our myoblast-based model of P3F-initiated tumorigenesis, and performed IHC staining of 63 human aRMS samples from tissue microarrays. Using constitutive and inducible RNAi, we examined the impact of TAZ loss of function on aRMS oncogenic phenotypes
and tumorigenesis
Finally, we performed pharmacologic studies in aRMS cell lines using porphyrin compounds, which interfere with TAZ-TEAD transcriptional activity.
TAZ is upregulated in our P3F-initiated aRMS model, and aRMS cells and tumors have high nuclear TAZ expression.
, TAZ suppression inhibits aRMS cell proliferation, induces apoptosis, supports myogenic differentiation, and reduces aRMS cell stemness. TAZ-deficient aRMS cells are enriched in G
-M phase of the cell cycle.
, TAZ suppression attenuates aRMS xenograft tumor growth. Preclinical studies show decreased aRMS xenograft tumor growth with porphyrin compounds alone and in combination with vincristine.
TAZ is oncogenic in aRMS sarcomagenesis. While P3F is currently not therapeutically tractable, targeting TAZ could be a promising novel approach in aRMS.
.</abstract><cop>United States</cop><pub>American Association for Cancer Research Inc</pub><pmid>29514840</pmid><doi>10.1158/1078-0432.CCR-17-1207</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Alveoli Animals Apoptosis Apoptosis - genetics Carcinoma Cell cycle Cell Cycle - genetics Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism Children Disease Models, Animal DNA microarrays Experimental design Forkhead Box Protein O1 - genetics Forkhead Box Protein O1 - metabolism FOXO1 protein Fusion protein Gene Expression Regulation, Neoplastic Heterografts Humans In vivo methods and tests Mice Myoblasts - metabolism Pax3 protein PAX3 Transcription Factor - genetics PAX3 Transcription Factor - metabolism Pharmacology Phenotypes Rhabdomyosarcoma Rhabdomyosarcoma, Alveolar - genetics Rhabdomyosarcoma, Alveolar - metabolism RNA-mediated interference Sarcoma Soft tissue sarcoma Trans-Activators Transcription Transcription Factors - genetics Transcription Factors - metabolism Transcriptional Activation Tumorigenesis Tumors Vincristine Xenografts Xenotransplantation |
| title | The Transcriptional Coactivator TAZ Is a Potent Mediator of Alveolar Rhabdomyosarcoma Tumorigenesis |
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