Aberrant AKT activation drives well-differentiated liposarcoma
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 1073/pnas.1106127108/-/DCSupplemental.
| Main Authors: | , , , , , , , , , , , , , , , |
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| Language: | en_US |
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Proceedings of the National Academy of Sciences (PNAS)
2012
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| Online Access: | http://hdl.handle.net/1721.1/70023 |
| _version_ | 1826199722992336896 |
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| author | Gutierrez, Alejandro Snyder, Eric Marino-Enriquez, Adrian Zhang, Yi-Xiang Sioletic, Stefano Kozakewich, Elena Grebliunaite, Ruta Ou, Wen-bin Sicinska, Ewa Raut, Chandrajit P. Demetri, George D. Perez-Atayde, Antonio R. Wagner, Andrew J. Fletcher, Jonathan A. Fletcher, Christopher D. M. Look, A. Thomas |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Gutierrez, Alejandro Snyder, Eric Marino-Enriquez, Adrian Zhang, Yi-Xiang Sioletic, Stefano Kozakewich, Elena Grebliunaite, Ruta Ou, Wen-bin Sicinska, Ewa Raut, Chandrajit P. Demetri, George D. Perez-Atayde, Antonio R. Wagner, Andrew J. Fletcher, Jonathan A. Fletcher, Christopher D. M. Look, A. Thomas |
| author_sort | Gutierrez, Alejandro |
| collection | MIT |
| description | This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.
1073/pnas.1106127108/-/DCSupplemental. |
| first_indexed | 2024-09-23T11:25:02Z |
| format | Article |
| id | mit-1721.1/70023 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:25:02Z |
| publishDate | 2012 |
| publisher | Proceedings of the National Academy of Sciences (PNAS) |
| record_format | dspace |
| spelling | mit-1721.1/700232022-09-27T19:22:24Z Aberrant AKT activation drives well-differentiated liposarcoma Gutierrez, Alejandro Snyder, Eric Marino-Enriquez, Adrian Zhang, Yi-Xiang Sioletic, Stefano Kozakewich, Elena Grebliunaite, Ruta Ou, Wen-bin Sicinska, Ewa Raut, Chandrajit P. Demetri, George D. Perez-Atayde, Antonio R. Wagner, Andrew J. Fletcher, Jonathan A. Fletcher, Christopher D. M. Look, A. Thomas Koch Institute for Integrative Cancer Research at MIT Snyder, Eric Snyder, Eric This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 1073/pnas.1106127108/-/DCSupplemental. Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebrafish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in p53 wild-type zebrafish, 6% in p53 heterozygotes, and 29% in p53-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS pathogenesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphorylation in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma. Ludwig Center at Dana-Farber/Harvard Cancer Center and Harvard Medical School Harvard Catalyst National Institutes of Health (U.S.) (Award UL1 RR 025758) Harvard University National Institutes of Health (U.S.) (Grant 1K08CA133103) Fundación Alfonso Martín Escudero 2012-04-13T17:13:31Z 2012-04-13T17:13:31Z 2011-09 2011-04 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/70023 Gutierrez, A. et al. “Aberrant AKT Activation Drives Well-differentiated Liposarcoma.” Proceedings of the National Academy of Sciences 108.39 (2011): 16386–16391. Web. 13 Apr. 2012. en_US http://dx.doi.org/10.1073/pnas.1106127108 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences (PNAS) PNAS |
| spellingShingle | Gutierrez, Alejandro Snyder, Eric Marino-Enriquez, Adrian Zhang, Yi-Xiang Sioletic, Stefano Kozakewich, Elena Grebliunaite, Ruta Ou, Wen-bin Sicinska, Ewa Raut, Chandrajit P. Demetri, George D. Perez-Atayde, Antonio R. Wagner, Andrew J. Fletcher, Jonathan A. Fletcher, Christopher D. M. Look, A. Thomas Aberrant AKT activation drives well-differentiated liposarcoma |
| title | Aberrant AKT activation drives well-differentiated liposarcoma |
| title_full | Aberrant AKT activation drives well-differentiated liposarcoma |
| title_fullStr | Aberrant AKT activation drives well-differentiated liposarcoma |
| title_full_unstemmed | Aberrant AKT activation drives well-differentiated liposarcoma |
| title_short | Aberrant AKT activation drives well-differentiated liposarcoma |
| title_sort | aberrant akt activation drives well differentiated liposarcoma |
| url | http://hdl.handle.net/1721.1/70023 |
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