Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma

BMC Cancer

Research Article

Maria G Tsokos¹  Jacqueline Talarchek²  Joseph R Testa²  Mitchell Cheung²  Ira Pastan³  Liqiang Xi⁴  Mark Raffeld⁴  Markku Miettinen⁴  Sandra Burkett⁵  Raffit Hassan⁶  Jingli Zhang⁶  Anish Thomas⁶  Yuanbin Chen⁶  Neetu Kalra⁶ 

[1] Beth Israel Deaconess Medical Center, Harvard Medical School, 02215, Boston, MA, USA;Cancer Biology Program, Fox Chase Cancer Center, 19111, Philadelphia, PA, USA;Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA;Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA;Molecular Cytogenetics Core Facility, National Cancer Institute, 21702, Frederick, MD, USA;Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 20892, Bethesda, MD, USA;

关键词: Mesothelioma;    Malignant effusions;    BAP1;    CDKN2A;    Patient derived tumor xenografts;   

DOI  :  10.1186/s12885-015-1362-2

 received in 2014-10-13, accepted in 2015-04-24,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundThe development and evaluation of new therapeutic approaches for malignant mesothelioma has been sparse due, in part, to lack of suitable tumor models.MethodsWe established primary mesothelioma cultures from pleural and ascitic fluids of five patients with advanced mesothelioma. Electron microscopy and immunohistochemistry (IHC) confirmed their mesothelial origin. Patient derived xenografts were generated by injecting the cells in nude or SCID mice, and malignant potential of the cells was analyzed by soft agar colony assay. Molecular profiles of the primary patient tumors, early passage cell cultures, and patient derived xenografts were assessed using mutational analysis, fluorescence in situ hybridization (FISH) analysis and IHC.ResultsPrimary cultures from all five tumors exhibited morphologic and IHC features consistent to those of mesothelioma cells. Mutations of BAP1 and CDKN2A were each detected in four tumors. BAP1 mutation was associated with the lack of expression of BAP1 protein. Three cell cultures, all of which were derived from BAP1 mutant primary tumors, exhibited anchorage independent growth and also formed tumors in mice, suggesting that BAP1 loss may enhance tumor growth in vivo. Both early passage cell cultures and mouse xenograft tumors harbored BAP1 mutations and CDKN2A deletions identical to those found in the corresponding primary patient tumors.ConclusionsThe mesothelioma patient derived tumor xenografts with mutational alterations that mimic those observed in patient tumors which we established can be used for preclinical development of novel drug regimens and for studying the functional aspects of BAP1 biology in mesothelioma.

【 授权许可】

Unknown   
© Kalra et al.; licensee BioMed Central. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.