title: Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma.
abstract: 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.
authors.affiliation: Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. neetu.kalra@gmail.com.
authors.forename: Neetu
authors.initials: N
authors.lastname: Kalra
authors.affiliation: Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. zhangjingl@mail.nih.gov.
authors.forename: Jingli
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. anish.thomas@nih.gov.
authors.forename: Anish
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. xil2@mail.nih.gov.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Xi
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. mitchell.cheung@fccc.edu.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Cheung
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. jacqueline.talarchek@fccc.edu.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Talarchek
authors.affiliation: Molecular Cytogenetics Core Facility, National Cancer Institute, Frederick, MD, 21702, USA. burketts@mail.nih.gov.
authors.forename: Sandra
authors.initials: S
authors.lastname: Burkett
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. mtsokos@bidmc.harvard.edu.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Tsokos
authors.affiliation: Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. ychenmd@gmail.com.
authors.forename: Yuanbin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. mraff@mail.nih.gov.
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. miettinenmm@mail.nih.gov.
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. pastani@mail.nih.gov.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. Joseph.Testa@fccc.edu.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
authors.affiliation: Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. hassanr@mail.nih.gov.
authors.forename: Raffit
authors.initials: R
authors.lastname: Hassan
mesh_terms: D000368:Aged; D000818:Animals; D018929:Cell Culture Techniques; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D008654:Mesothelioma / Q000235:genetics / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D010997:Pleural Neoplasms / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D055815:Young Adult
chemical_list: C400134:BAP1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase