Molecular mechanisms of meningioma invasion: Function and therapeutic relevance of small GTPases in relation to NF2/Merlin

• Applicant: Professor Dr. Christian Mawrin
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Pathology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 265549829

Brain-invasive growth of meningioma comprises a highly-relevant clinical problem with negative effects on recurrency rates and overall survival. The knowledge regarding the mechanisms driving meningioma invasion are less-well characterized. The small GTPases RhoA, RAC-1, and cdc42 are important molecules for the regulation of tumor cell motility and -invasion. Few data suggest a role of RAC-1 in aggressive meningiomas, because activating mutations have been found in about 39% of meningiomas in one study. Furthermore, RAc-1 and cdc42 binds to PI3 kinase, which is known to be activated in aggressive/invasive meningiomas. Schwannoma cells with loss of the tumor suppressor NF2/merlin show increased activity of RAC-1 and cdc42. About 50 percent of sporadic human meningiomas are characterized by alterations of NF2, and meningeal knockdown of NF2 leads to meningioma formation in mice. It was recently reported that members of the Rho-GTPase signaling pathway are differentially expressed in meningiomas depending on the NF2 condition.In this project, we aim to define the role of RhoA, RAC-1, and cdc42 for the regulation of meningioma cell invasion and motility in relation the NF2/merlin in detail. We will use established cell culture models including syngenic pairs of meningioma cells with stable knockdown of NF2/merlin, as well as xenograft and genetic mouse models to define whether RhoA, RAC-1, or cdc42 are substantially involved in meningioma cell motility and invasion. The genetic meningioma model previously established by Michel Kalamarides (Paris) is based on Cre-mediated local NF2 knockdown and is already used in our laboratory. These mice can be crossed with floxed mice for each of the three GTPases, providing insight into their regulation of NF2-knockout based meningioma growth and brain invasion. To establish a potential therapeutic impact of GTPase signaling manipulation, we will study the Rho kinase (ROCK) inhibitor Fasudil using our well-established meningioma xenograft mouse model. We expect from the results of the project a significant improvement in the understanding of mechanisms driving meningioma cell invasion, especially in relation to NF2/merlin. The preclinical evaluation of specific inhibitors will bridge to new therapeutic options for meningioma patients not eligible for conventional treatment strategies like surgery or irradiation.

• DFG Programme: Research Grants