Meningioma Laboratory
The meningioma laboratory is investigating the genetic changes underlying meningioma tumorigenesis, with the eventual goal of improved therapy. Meningiomas are the most common primary intracranial brain tumor. They also occur in patients afflicted with Neurofibromatosis 2 (NF2), a cancer predisposition syndrome. Current treatment options, restricted to surgical resection and radiation therapy, are often inadequate because some meningiomas are not amenable to surgery and others recur even after surgery and radiation treatment. Also, the existing histopathological grading system does not adequately predict the rates of meningioma tumor growth or the likelihood of tumor recurrence.
We are using genomics to develop a molecular classification system for meningiomas. These studies promise to result in more precise predictions of clinical outcome, especially for atypical meningioma patients. In addition, we are particularly interested in deciphering the mechanism(s) by which NF2 functions as a tumor suppressor in meningiomas. Elucidating of downstream signaling mechanisms for NF2 is anticipated to lead to targeted therapies for these patients. Model Systems for meningiomas are rare. Our laboratory is also developing mouse models of meningiomas for preclinical testing of potential therapeutic agents.
Current Research Projects
Predicting prognosis of atypical meningioma patients using molecular signature
Using gene expression analysis, we have shown that meningiomas of all histopathological grades cluster in two major molecular groups: “low proliferative” and ‘high proliferative” meningiomas. While all benign meningiomas fall into the low-proliferative group and all malignant meningiomas fall into the high-proliferative group, atypical meningiomas distribute into either one of these groups. Atypical meningiomas demonstrate the widest variability in clinical behavior, and distribute into either one of these groups, suggesting that molecular signatures can distinguish slower-growing, more indolent atypical tumors from the more aggressive ones. We have also identified a set of 33 classifier genes that precisely distinguish meningiomas of either molecular group. Current studies are focused on using these classifier genes to stratify atypical meningiomas into molecular groups that result in more precise predictions of clinical outcome. It is anticipated that these findings will have a significant impact in predicting the prognosis of atypical meningioma patients and in defining treatment regimens.
Merlin and the Hippo pathway in meningiomas
The mechanism by which loss of the neurofibromatosis 2 (NF2) gene contributes to neoplasia is not entirely clear. In Drosophila, the NF2 gene product, merlin, controls cell proliferation and apoptosis by signaling through the Hippo pathway to inhibit the function of the transcriptional coactivator Yorkie. The Hippo pathway is conserved in mammals. We have developed human meningioma cell lines matched for merlin expression and are investigating the relationship between NF2 status and Yes-associated protein (YAP), the mammalian homolog of Yorkie. NF2 loss in meningioma cells is associated with loss of contact-dependent growth inhibition, enhanced anchorage-independent growth and increased cell proliferation due to increased S-phase entry. Merlin loss in both meningioma cell lines and primary tumors results in increased YAP expression and nuclear localization. In addition, shRNA-mediated reduction of YAP in NF2-deficient meningioma cells rescued the effects of merlin loss on cell proliferation and S-phase entry. These results demonstrate that merlin regulates cell growth in meningiomas by suppressing YAP. We are currently linking merlin status to other components of the Hippo pathway, and anticipate that this signaling pathway could be exploited for therapeutic purposes.
Aberrant Notch signaling in meningiomas
Gene expression analysis on a panel of primary meningiomas of all grades revealed that components of the Notch signaling pathway are deregulated. The Notch signaling axis regulates cell fate specification and stem cell maintenance during normal development. Aberrant Notch signaling has an important role on the growth and survival in several cancer types, with Notch pathway genes functioning as oncogenes or tumor suppressors in different cancers. Therefore, we were interested in evaluating the functional consequence of abnormal Notch signaling in meningiomas. Exogenous expression of activated Notch1 and Notch2 receptors and the Notch downstream effector, HES1, induce a tetraploid phenotype in meningioma cell lines. These tetraploid cells are associated with features of chromosomal instability and exhibit enhanced acquisition of numerical and structural chromosomal abnormalities. Primary meningioma tumors contain tetraploid cells that possess nuclear features of chromosomal instability and have activated Notch signaling. These results suggest that deregulated expression of the Notch pathway is a critical event in meningioma pathogenesis and potentially promotes tumor development.
Development of meningioma model systems
Crucial to understanding the role of individual genes in meningioma pathogenesis is the availability of tumor model systems that recapitulate essential features of the human disease. Meningioma model systems are rare and most studies have relied on using primary cultures of meningiomas, which have limited utility. Our laboratory has successfully overcome the cellular senescence of primary meningiomas cell lines and developed a wide spectrum of cell lines by expressing the human papillomavirus E6/E7 oncogenes and/or the telomerase catalytic subunit. We have also developed an orthotopic skull-base malignant meningioma model in athymic mice and use bioluminescent imaging to non-invasively monitor their growth. This preclinical model is being used to determine the survival benefit of therapeutic agents.
Defining meningioma stem cell population
Cancer stem cells (CSTs) are a subpopulation of cells within tumors with the greatest ability to proliferate and form new tumors. Understanding the nature of the CSC is essential to understanding the tumor biology of a given tumor and to develop effective therapies. There is nothing known about the characteristics of the putative CSC in meningiomas. We are characterizing the self-renewal and differentiation capabilities of neruospheres isolated from fresh meningioma tumors, and are assessing the expression of mesenchymal stem cell markers. Access to this tumorigenic subpopulation will lead to the development of more representative model systems.