Abstract
Simple SummaryThe Microtubule-associated protein Tau is expressed in different cancers; however, its role and prognostic value are still debated. In the present work, we evaluated the role of Tau in glioblastoma by down-regulating its expression in glioblastoma cells. We showed that Tau: (1) is required for tumor progression in nude mice; (2) is necessary for glioblastoma 3D cell organization, growth, and migration; and (3) regulates the PI3K/AKT signaling pathway.The Microtubule-Associated Protein Tau is expressed in several cancers, including low-grade gliomas and glioblastomas. We have previously shown that Tau is crucial for the 2D motility of several glioblastoma cell lines, including U87-MG cells. Using an RNA interference (shRNA), we tested if Tau contributed to glioblastoma in vivo tumorigenicity and analyzed its function in a 3D model of multicellular spheroids (MCS). Tau depletion significantly increased median mouse survival in an orthotopic glioblastoma xenograft model. This was accompanied by the inhibition of MCS growth and cell evasion, as well as decreased MCS compactness, implying N-cadherin mislocalization. Intracellular Signaling Array analysis revealed a defective activation of the PI3K/AKT pathway in Tau-depleted cells. Such a defect in PI3K/AKT signaling was responsible for reduced MCS growth and cell evasion, as demonstrated by the inhibition of the pathway in control MCS using LY294002 or Perifosine, which did not significantly affect Tau-depleted MCS. Finally, analysis of the glioblastoma TCGA dataset showed a positive correlation between the amount of phosphorylated Akt-Ser473 and the expression of MAPT RNA encoding Tau, underlining the relevance of our findings in glioblastoma disease. We suggest a role for Tau in glioblastoma by controlling 3D cell organization and functions via the PI3K/AKT signaling axis.
Highlights
IntroductionGlioblastomas (grade IV of gliomas, GBM) are the most frequent primary tumors of the central nervous system
Introduction distributed under the terms andGlioblastomas are the most frequent primary tumors of the central nervous system
The analysis of N-cadherin expression and localization at the cell membrane was not affected by Tau down-regulation in 2D-cultured adherent cells (Supplementary Figure S4). These results suggest that Tau may be involved in the stabilization of N-cadherin to the actin cytoskeleton at the cell–cell contacts in multicellular spheroids (MCS), linking Tau and N-Cadherin in 3D cell organization
Summary
Glioblastomas (grade IV of gliomas, GBM) are the most frequent primary tumors of the central nervous system. They are very aggressive, highly angiogenic, and associated with a very bad prognosis. They account for 52% to 75% of diagnosed gliomas with a median patient survival of 15 months [1,2]. The invasive and angiogenic phenotype of GBM tumors renders surgical tumor resection difficult and limits the efficacy of current radiotherapy and chemotherapy. The search for new targets and therapeutic approaches is still a current challenge
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