Regulation of glioma cell invasion by 3q26 gene products PIK3CA, SOX2 and OPA1

Abstract

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.

SOX2 protein biochemistry in stemness, reprogramming, and cancer: the PI3K/AKT/SOX2 axis and beyond

“…In patients with breast or ovarian cancer for example, SOX2 induction is already observed at early disease stages and further associates with disease progression, metastasis, and relapse [40,43,45,46]. In glioblastoma as another example, elevated SOX2 expression associates with increased cell motility and tumor spreading and is also detected amongst circulating CSC islets [49][50][51]. Further involving SOX2 in cancer stemness, elevated SOX2 expression associates with chemotherapyresistance effects [52], induces stemness and endothelial-tomesenchymal-transition gene signatures [17], and promotes clonogenicity and in vivo tumorigenicity in respective model systems [43,52].…”

“…Interestingly, cancers of immanent high SOX2 expression often show intrinsically high mutations rates in PI3KCA or PTEN genes as well [50,64], thus suggesting functional connectivity between PI3K/AKT signaling and stemness-inductory roles of SOX2.…”

“…The dependencies between PI3K/AKT and SOX2 however are reciprocal, as probably best exemplified in glioblastoma, where PI3K/AKT-imposed phosphorylation sustains nuclear SOX2 expression as a driving force of tumor cell dissemination, while in turn SOX2 supports PI3KCA gene expression (which actually locates in near juxtaposition of the SOX2 locus on chromosome band 3q26-28) and subsequent downstream activation of AKT [50]. Similarly, SOX2 and KLF4 jointly drive PIK3CA expression in nasopharyngeal carcinoma, thus enhancing PI3K/AKT activity and tumorigenesis, while overexpression of PI3KCA rescues growth inhibitory effects imposed by SOX2 knock-down [18].…”

“…2 for schematic illustration). This distinction is underscored by experimental evidence indicating that various AKT or PI3K inhibitors, but not the mTORC1 selective inhibitor rapamycin, affect SOX2 protein homeostasis in several tumor entities [50,52]. However, inhibition of mTORC1 has also been described to attenuate SOX2 and further downstream SOX9 expression in glioma [102], and both PI3K inhibitors and rapamycin reported to suppress SOX2-driven tumorigenicity from esophageal squamous cells in a murine xenografts [103].…”

Glioblastoma molecular and histological heterogeneity

“…Белок, кодируемый этим геном, представляет собой каталитическую субъединицу, которая играет ключевую роль в активации сигнальных каскадов, участвующих в клеточном росте, выживании, пролиферации, подвижности и формировании внутренней структуры [27]. T. Schaefer с коллегами показали, что PIK3CA вместе с белками AKT1 и SOX2 взаимосвязаны с процессами деления митохондрий, формируя общую сигнальную сеть, регулирующую инвазивность клеток астроцитарных глиом [28]. Кроме того, L.H.…”