PMID- 25952750 OWN - NLM STAT- MEDLINE DCOM- 20160125 LR - 20201218 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 15 DP - 2015 May 8 TI - Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma. PG - 376 LID - 10.1186/s12885-015-1362-2 [doi] LID - 376 AB - BACKGROUND: The development and evaluation of new therapeutic approaches for malignant mesothelioma has been sparse due, in part, to lack of suitable tumor models. METHODS: We 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. RESULTS: Primary 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. CONCLUSIONS: The 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. FAU - Kalra, Neetu AU - Kalra N AD - Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. neetu.kalra@gmail.com. FAU - Zhang, Jingli AU - Zhang J AD - Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. zhangjingl@mail.nih.gov. FAU - Thomas, Anish AU - Thomas A AD - Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. anish.thomas@nih.gov. FAU - Xi, Liqiang AU - Xi L AD - Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. xil2@mail.nih.gov. FAU - Cheung, Mitchell AU - Cheung M AD - Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. mitchell.cheung@fccc.edu. FAU - Talarchek, Jacqueline AU - Talarchek J AD - Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. jacqueline.talarchek@fccc.edu. FAU - Burkett, Sandra AU - Burkett S AD - Molecular Cytogenetics Core Facility, National Cancer Institute, Frederick, MD, 21702, USA. burketts@mail.nih.gov. FAU - Tsokos, Maria G AU - Tsokos MG AD - Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. mtsokos@bidmc.harvard.edu. FAU - Chen, Yuanbin AU - Chen Y AD - Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. ychenmd@gmail.com. FAU - Raffeld, Mark AU - Raffeld M AD - Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. mraff@mail.nih.gov. FAU - Miettinen, Markku AU - Miettinen M AD - Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. miettinenmm@mail.nih.gov. FAU - Pastan, Ira AU - Pastan I AD - Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. pastani@mail.nih.gov. FAU - Testa, Joseph R AU - Testa JR AD - Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. Joseph.Testa@fccc.edu. FAU - Hassan, Raffit AU - Hassan R AD - Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. hassanr@mail.nih.gov. LA - eng GR - P30 ES013508/ES/NIEHS NIH HHS/United States GR - R01 CA175691/CA/NCI NIH HHS/United States GR - Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20150508 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (BAP1 protein, human) RN - 0 (Cyclin-Dependent Kinase Inhibitor p16) RN - 0 (Tumor Suppressor Proteins) RN - EC 3.4.19.12 (Ubiquitin Thiolesterase) SB - IM MH - Aged MH - Animals MH - Cell Culture Techniques MH - Cyclin-Dependent Kinase Inhibitor p16/*genetics MH - Female MH - Humans MH - Lung Neoplasms/genetics/*pathology MH - Male MH - Mesothelioma/genetics/*pathology MH - Mesothelioma, Malignant MH - Mice MH - Mice, Nude MH - Mice, SCID MH - Middle Aged MH - *Mutation MH - Neoplasm Transplantation MH - Neoplasms, Experimental MH - Pleural Neoplasms/genetics/*pathology MH - Tumor Cells, Cultured MH - Tumor Suppressor Proteins/*genetics MH - Ubiquitin Thiolesterase/*genetics MH - Young Adult PMC - PMC4431029 EDAT- 2015/05/09 06:00 MHDA- 2016/01/26 06:00 PMCR- 2015/05/08 CRDT- 2015/05/09 06:00 PHST- 2014/10/13 00:00 [received] PHST- 2015/04/24 00:00 [accepted] PHST- 2015/05/09 06:00 [entrez] PHST- 2015/05/09 06:00 [pubmed] PHST- 2016/01/26 06:00 [medline] PHST- 2015/05/08 00:00 [pmc-release] AID - 10.1186/s12885-015-1362-2 [pii] AID - 1362 [pii] AID - 10.1186/s12885-015-1362-2 [doi] PST - epublish SO - BMC Cancer. 2015 May 8;15:376. doi: 10.1186/s12885-015-1362-2.