Abstract
BACKGROUND: Diffuse gliomas progress by invading neighboring brain tissue to promote post-operative relapse. Transcription factor gene SOX2 is highly expressed in invasive gliomas and maps to 3q26 together with the genes for the PI3K/AKT signaling activator PIK3CA, and those encoding effectors of mitochondria fusion and cell invasion inhibitors MFN1 and OPA1. MATERIAL AND METHODS: We aimed at investigating their respective roles in glioma cell invasion in vitro and by exploiting retrospective patient neuro-imaging data. RESULTS: Gene copy number analysis at 3q26 from 129 glioma patient biopsies revealed mutually exclusive SOX2amplifications (26%) and OPA1losses (19%). Both forced SOX2expression and OPA1inactivation increased LN319 glioma cell invasion. Conversely, pharmacological PI3K/AKT pathway inhibition decreased invasion and resulted in SOX2 nucleus-to-cytoplasm translocation in a mTORC1-independent manner, showing that PI3K/AKT signaling sustains SOX2 activity. Chromatin immuno-precipitation and luciferase reporter gene assays together demonstrated that SOX2 trans-activates PIK3CAandOPA1. Thus, SOX2 activates PI3K/AKT signaling in a positive feedback loop, while OPA1 deletion is interpreted to counter-act OPA1 trans-activation. Remarkably, neuro-imaging of human gliomas with high SOX2or low OPA1genomic imbalances revealed significantly larger necrotic tumor zone volumes, corresponding to higher invasive capacities of tumors. Whereas glioma invasion is activated by a PI3K/AKT-SOX2 loop, it is reduced by a cryptic invasion suppressor SOX2-OPA1 pathway. CONCLUSION: RTK/PI3K/AKT-SOX2 and mitochondria fission represent potential signaling networks to be targeted to control glioma invasion. In addition, our results indicate that necrosis volume is a potential surrogate marker for evaluation of invasion.