Person:

Ramesh, Vijaya

Background: Meningiomas may occur either as familial tumors in two distinct disorders, familial multiple meningioma and neurofibromatosis 2 (NF2), or sporadically, as either single or multiple tumors in individuals with no family history. Meningiomas in NF2 and approximately 60% of sporadic meningiomas involve inactivation of the NF2 locus, encoding the tumor suppressor merlin on chromosome 22q. This study was undertaken to establish whether genomic profiling could distinguish familial multiple meningiomas from sporadic solitary and sporadic multiple meningiomas. Methods: We compared 73 meningiomas presenting as sporadic solitary (64), sporadic multiple (5) and familial multiple (4) tumors using genomic profiling by array comparative genomic hybridization (array CGH). Results: Sporadic solitary meningiomas revealed genomic rearrangements consistent with at least two mechanisms of tumor initiation, as unsupervised cluster analysis readily distinguished tumors with chromosome 22 deletion (associated with loss of the NF2 tumor suppressor) from those without chromosome 22 deletion. Whereas sporadic meningiomas without chromosome 22 loss exhibited fewer chromosomal imbalance events overall, tumors with chromosome 22 deletion further clustered into two major groups that largely, though not perfectly, matched with their benign (WHO Grade I) or advanced (WHO Grades II and III) histological grade, with the latter exhibiting a significantly greater degree of genomic imbalance (P < 0.001). Sporadic multiple meningiomas showed a frequency of genomic imbalance events comparable to the atypical grade solitary tumors. By contrast, familial multiple meningiomas displayed no imbalances, supporting a distinct mechanism for the origin for these tumors. Conclusion: Genomic profiling can provide an unbiased adjunct to traditional meningioma classification and provides a basis for exploring the different genetic underpinnings of tumor initiation and progression. Most importantly, the striking difference observed between sporadic and familial multiple meningiomas indicates that genomic profiling can provide valuable information for differential diagnosis of subjects with multiple meningiomas and for considering the risk for tumor occurrence in their family members.

Meningiomas, common tumors arising from arachnoidal cells of the meninges, may occur sporadically, or in association with the inherited disorder, neurofibromatosis 2 (NF2). Most sporadic meningiomas result from NF2 inactivation, resulting in loss of tumor suppressor merlin, implicated in regulating membrane-cytoskeletal organization. To investigate merlin function in an authentic target cell type for NF2 tumor formation, we established primary cultures from genetically-matched meningioma and normal arachnoidal tissues. Our studies revealed novel and distinct cell biological and biochemical properties unique to merlin-deficient meningioma cells compared to merlin-expressing arachnoidal and meningioma cells, and other NF2-deficient cell types. Merlin-deficient meningioma cells displayed cytoskeletal and cell contact defects, altered cell morphology and growth properties, most notably cell senescence, implicating the activation of senescence pathways in limiting benign meningioma growth. Merlin suppression by RNAi in arachnoidal cells replicated merlin-deficient meningioma features, thus establishing these cell systems as disease-relevant models for studying NF2 tumorigenesis.

Inactivating mutations of the neurofibromatosis 2 (NF2) gene, NF2, result predominantly in benign neurological tumors, schwannomas and meningiomas, in humans; however, mutations in murine Nf2 lead to a broad spectrum of cancerous tumors. The tumor-suppressive function of the NF2 protein, merlin, a membrane-cytoskeleton linker, remains unclear. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a novel mediator of merlin's tumor suppressor activity. Merlin-deficient human meningioma cells and merlin knockdown arachnoidal cells, the nonneoplastic cell counterparts of meningiomas, exhibit rapamycin-sensitive constitutive mTORC1 activation and increased growth. NF2 patient tumors and Nf2-deficient mouse embryonic fibroblasts demonstrate elevated mTORC1 signaling. Conversely, the exogenous expression of wild-type merlin isoforms, but not a patient-derived L64P mutant, suppresses mTORC1 signaling. Merlin does not regulate mTORC1 via the established mechanism of phosphoinositide 3-kinase-Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase-mediated TSC2 inactivation and may instead regulate TSC/mTOR signaling in a novel fashion. In conclusion, the deregulation of mTORC1 activation underlies the aberrant growth and proliferation of NF2-associated tumors and may restrain the growth of these lesions through negative feedback mechanisms, suggesting that rapamycin in combination with phosphoinositide 3-kinase inhibitors may be therapeutic for NF2.