Diffuse gliomas progress by invading neighboring brain tissue to promote postoperative relapse. Transcription factor SOX2 is highly expressed in invasive gliomas and maps to chromosome region 3q26 together with the genes for PI3K/AKT signaling activator PIK3CA and effector molecules of mitochondria fusion and cell invasion, MFN1 and OPA1. Gene copy number analysis at 3q26 from 129 glioma patient biopsies revealed mutually exclusive SOX2 amplifications (26%) and OPA1 losses (19%). Both forced SOX2 expression and OPA1 inactivation increased LN319 glioma cell invasion in vitro and promoted cell dispersion in vivo in xenotransplanted D. rerio embryos. While PI3 kinase activity sustained SOX2 expression, pharmacological PI3K/AKT pathway inhibition decreased invasion and resulted in SOX2 nucleus‐to‐cytoplasm translocation in an mTORC1‐independent manner. Chromatin immunoprecipitation and luciferase reporter gene assays together demonstrated that SOX2 trans‐activates PIK3CA and OPA1. Thus, SOX2 activates PI3K/AKT signaling in a positive feedback loop, while OPA1 deletion is interpreted to counteract OPA1 trans‐activation. Remarkably, neuroimaging of human gliomas with high SOX2 or low OPA1 genomic imbalances revealed significantly larger necrotic tumor zone volumes, corresponding to higher invasive capacities of tumors, while autologous necrotic cells are capable of inducing higher invasion in SOX2 overexpressing or OPA1 knocked‐down relative to parental LN319. We thus propose necrosis volume as a surrogate marker for the assessment of glioma invasive potential. Whereas glioma invasion is activated by a PI3K/AKT‐SOX2 loop, it is reduced by a cryptic invasion suppressor SOX2‐OPA1 pathway. Thus, PI3K/AKT‐SOX2 and mitochondria fission represent connected signaling networks regulating glioma invasion.

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Gliomas are the most frequent and the most aggressive tumors of CNS. Invasiveness and existence of glioma stem-like cells resistant to conventional therapy contribute to the aggressive phenotype of the tumor. Current treatment efforts (surgery and radiation therapy) fail to prevent the relapse of secondary gliomas. Measurement of thickness of the infiltration zone surrounding the tumor mass, visualized by MRI, allows classification of patient glioma into Grade I (2-3 mm), Grade II (3-10 mm) and Grade III (>10 mm). Microarray data from classified biopsies indicate that SOX2 and HEY1 mRNAs expressions correlated with tumor invasion grade. This suggested a possible role for SOX2 and HEY1 in regulating genes involved in invasion. Lentiviruses expressing shRNAs against either SOX2 or HEY1 were used to knockdown human glioma cell lines U373 and LN319. Boyden chamber assays and wound healing assays were used as readouts for invasion and migration respectively. Gene expression analysis on glioma cells depleted for SOX2 revealed 2-5 fold down-regulation of HEY1 mRNA. Interestingly, we observed that glioma cells depleted for HEY1 showed 1-1.5 fold up-regulation for SOX2. This suggested that these transcription factors could be regulating each other. We observed that invasion and migration was strongly enhanced in SOX2 depleted cells. Consistently, our microarray data on these cells showed that mRNA of genes related to epithelial-mesenchymal-transition (EMT) were 1-3.5 fold overexpressed. In contrast, glioma cells depleted for HEY1 showed significant reduction in invasion and migration and the mRNA of genes related to EMT were 2- 5-fold downregulated. These results are consistent in supporting the hypothesis that a SOX2- HEY1 signaling loop participates in EMT and in glioma invasion. Confirmation of these observations is currently being carried out on a genetic mice model of glioma. Definition of the effectors of glioma invasion might ultimately contribute to identify targets for the development of customized therapies aimed at controlling glioma invasion. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B168. Citation Format: Archana Ramadoss, Jean Louis Boulay, Cristobal Tostado, Marie-Francoisse Ritz, Luigi Mariani. Investigating the role of SOX2- HEY1 signaling loop in Glioma Invasion. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B168.