title: Tumor suppressor alterations cooperate to drive aggressive mesotheliomas with enriched cancer stem cells via a p53-miR-34a-c-Met axis.
abstract: Malignant mesothelioma is a highly aggressive, asbestos-related cancer frequently marked by mutations of both NF2 and CDKN2A. We demonstrate that germline knockout of one allele of each of these genes causes accelerated onset and progression of asbestos-induced malignant mesothelioma compared with asbestos-exposed Nf2(+/-) or wild-type mice. Ascites from some Nf2(+/-);Cdkn2a(+/-) mice exhibited large tumor spheroids, and tail vein injections of malignant mesothelioma cells established from these mice, but not from Nf2(+/-) or wild-type mice, produced numerous tumors in the lung, suggesting increased metastatic potential of tumor cells from Nf2(+/-);Cdkn2a(+/-) mice. Intraperitoneal injections of malignant mesothelioma cells derived from Nf2(+/-);Cdkn2a(+/-) mice into severe combined immunodeficient mice produced tumors that penetrated the diaphragm and pleural cavity and harbored increased cancer stem cells (CSC). Malignant mesothelioma cells from Nf2(+/-);Cdkn2a(+/-) mice stained positively for CSC markers and formed CSC spheroids in vitro more efficiently than counterparts from wild-type mice. Moreover, tumor cells from Nf2(+/-);Cdkn2a(+/-) mice showed elevated c-Met expression/activation, which was partly dependent on p53-mediated regulation of miR-34a and required for tumor migration/invasiveness and maintenance of the CSC population. Collectively, these studies demonstrate in vivo that inactivation of Nf2 and Cdkn2a cooperate to drive the development of highly aggressive malignant mesotheliomas characterized by enhanced tumor spreading capability and the presence of a CSC population associated with p53/miR-34a-dependent activation of c-Met. These findings suggest that cooperativity between losses of Nf2 and Cdkn2a plays a fundamental role in driving the highly aggressive tumorigenic phenotype considered to be a hallmark of malignant mesothelioma.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Menges
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Yuwaraj
authors.initials: Y
authors.lastname: Kadariya
authors.affiliation: Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32827.
authors.forename: Deborah
authors.initials: D
authors.lastname: Altomare
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Talarchek
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Erin
authors.initials: E
authors.lastname: Neumann-Domer
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111.|Cancer Research Institute, Southern Medical University, Guangdong Province, PR China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangdong Province, PR China.
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Xiao
authors.affiliation: Verastem Inc., Cambridge MA 02142.
authors.forename: Irina M
authors.initials: IM
authors.lastname: Shapiro
authors.affiliation: Verastem Inc., Cambridge MA 02142.
authors.forename: Vihren N
authors.initials: VN
authors.lastname: Kolev
authors.affiliation: Verastem Inc., Cambridge MA 02142.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Pachter
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
mesh_terms: D000818:Animals; D001194:Asbestos; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016515:Genes, Neurofibromatosis 2 / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology; D009154:Mutation; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000502:physiology*; D010997:Pleural Neoplasms / Q000235:genetics* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D001194:Asbestos; D019859:Proto-Oncogene Proteins c-met