From Fox Chase: "...inactivation of Nf2 and Cdkn2a cooperate to drive the development of highly aggressive malignant mesotheliomas..."

Cancer Res. 2013 Dec 26. [Epub ahead of print]

Tumor Suppressor Alterations Cooperate to Drive Aggressive Mesotheliomas with Enriched Cancer Stem Cells via a p53-miR34a-c-Met Axis.

Menges CW, Kadariya Y, Altomare D, Talarchek J, Neumann-Domer E, Wu Y, Xiao GH, Shapiro IM, Kolev VN, Pachter JA, Klein-Szanto A, Testa JR.

Author information

• Cancer Biology Program, Fox Chase Cancer Center.

Abstract

Malignant mesothelioma (MM) 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 MM compared to asbestos-exposed Nf2+/- or wild-type (WT) mice. Ascites from some Nf2+/-;Cdkn2a+/- mice exhibited large tumor spheroids, and tail vein injections of MM cells established from these mice, but not from Nf2+/- or WT mice, produced numerous tumors in the lung, suggesting increased metastatic potential of tumor cells from Nf2+/-;Cdkn2a+/- mice. Intraperitoneal injections of MM cells derived from Nf2+/-;Cdkn2a+/- mice into SCID mice produced tumors that penetrated the diaphragm and pleural cavity and harbored an increased cancer stem cells (CSCs). MM cells from Nf2+/-;Cdkn2a+/- mice stained positively for CSC markers and formed CSC spheroids in vitro more efficiently than counterparts from WT mice. Moreover, tumor cells from Nf2+/-;Cdkn2a+/- mice showed elevated c-Met expression/activation, which was partly dependent on p53-mediated regulation of miR34a 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 MMs characterized by enhanced tumor spreading capability and the presence of a CSC population associated with p53/miR34a-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 MM.