Pagano Alessandra, Breuzard Gilles, Parat Fabrice, Tchoghandjian Aurélie, Figarella-Branger Dominique, De Bessa Tiphany Coralie, Garrouste Françoise, Douence Alexis, Barbier Pascale, Kovacic Hervé
Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), Team 9, UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France.
Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), Team 8, UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France.
Cancers (Basel). 2021 Nov 19;13(22):5818. doi: 10.3390/cancers13225818.
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 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.
微管相关蛋白Tau在多种癌症中表达，包括低级别胶质瘤和胶质母细胞瘤。我们之前已经表明，Tau对于包括U87-MG细胞在内的多种胶质母细胞瘤细胞系的二维运动至关重要。我们使用RNA干扰（shRNA）测试了Tau是否对胶质母细胞瘤的体内致瘤性有影响，并在多细胞球体（MCS）的三维模型中分析了其功能。在原位胶质母细胞瘤异种移植模型中，Tau的缺失显著提高了小鼠的中位生存期。这伴随着MCS生长的抑制和细胞逃逸，以及MCS紧实度的降低，这意味着N-钙黏蛋白定位错误。细胞内信号阵列分析显示，在Tau缺失的细胞中PI3K/AKT信号通路的激活存在缺陷。PI3K/AKT信号通路的这种缺陷导致了MCS生长的减少和细胞逃逸，使用LY294002或哌立福辛抑制对照MCS中的该信号通路就证明了这一点，而这对Tau缺失的MCS没有显著影响。最后，对胶质母细胞瘤TCGA数据集的分析显示，磷酸化的Akt-Ser473的量与编码Tau的RNA的表达之间存在正相关，突出了我们在胶质母细胞瘤疾病中的发现的相关性。我们认为Tau通过PI3K/AKT信号轴控制三维细胞组织和功能，在胶质母细胞瘤中发挥作用。
