Definition der Rolle von SMO, KLF4 und TERT Mutationen für die Aggressivität von Meningeomen in vitro und in vivo

The recently detected oncogenic mutations of SMO, KLF4, and in the TERT promoter in a subset of meningiomas, mainly without NF2-loss, suggest the existence of NF2-independent pathways of meningioma genesis. While mutations of SMO and KLF4 occur more frequently in low-grade meningiomas of special locations (median skull base) or of a single subtype (secretory meningiomas), activating mutations of the TERT promoter dominate in tumors of higher WHO grade, which possess a generally higher aggressiveness, including a tendency for brain invasion and early tumor recurrence.
Until now the available data, which link the new oncogenic mutations with relevant biologic features of meningiomas have mainly been derived from the frequency of these mutations in meningioma subtypes. Relevant data for their role in meningioma aggressiveness can only partially be deduced from these studies, i.e. evidences for a relation of TERT to higher grades and a significant effect on time to tumor recurrence, without a closer definition of the functional role of TERT promoter mutations in meningioma cells. For the other two genes (SMO, KLF4) only limited information can be drawn from the descriptive studies available so far. Interestingly recent data provided clues that the presence of SMO mutations in low-grade meningiomas promotes early tumor recurrence, while KLF4 mutations in skull base meningiomas might prevent tumor recurrence.
However, in cooperation with another subproject of a larger scientific cooperation - dedicated to the comparison of these mutations in recurrences vs. primary tumors and in invasive vs non-invasive regions - our subproject will analyze the role of all three mutations for meningioma aggressiveness by direct comparison of mutant vs. wild type genes in genetically engineered cells and xenografts. For this purpose, pairs of syngeneic meningioma cell lines will be constructed with a controlled low-level expression of the genes. These lines will be assayed in vitro and in vivo for their proliferation rate, cell motility, invasive potential, tumorigenic potency, impact on mouse survival, and susceptibility for targeted therapies including combined irradiation/drug treatment.