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

Neetu Kalra, Jingli Zhang, Anish Thomas, Liqiang Xi, Mitchell Cheung, Jacqueline Talarchek, Sandra Burkett, Maria G. Tsokos, Yuanbin Chen, Mark Raffeld, Markku Miettinen, Ira Pastan, Joseph R. Testa, Raffit Hassan

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish
Article number376
JournalBMC Cancer
Volume15
Issue number1
DOIs
StatePublished - May 8 2015

Keywords

  • BAP1
  • CDKN2A
  • Malignant effusions
  • Mesothelioma
  • Patient derived tumor xenografts

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