Roy Marie-Eve, Veilleux Carolane, Paquin Alexis, Gagnon Alexandre, Annabi Borhane
Laboratoire d'Oncologie Moléculaire.
Laboratoire de Chimie Organique et Médicinale, Département de Chimie, Université du Québec à Montréal, Montreal, Québec, Canada.
Anticancer Drugs. 2024 Sep 1;35(8):709-719. doi: 10.1097/CAD.0000000000001627. Epub 2024 Jun 18.
Glioblastoma (GBM) is a highly angiogenic malignancy of the central nervous system that resists standard antiangiogenic therapy, in part because of an alternative process to angiogenesis termed vasculogenic mimicry. Intricately linked to GBM, dysregulation of the Hippo signaling pathway leads to overexpression of YAP/TEAD and several downstream effectors involved in therapy resistance. Little is known about whether vasculogenic mimicry and the Hippo pathway intersect in the GBM chemoresistance phenotype. This study seeks to investigate the expression patterns of Hippo pathway regulators within clinically annotated GBM samples, examining their involvement in vitro regarding vasculogenic mimicry. In addition, it aims to assess the potential for pharmacological targeting of this pathway. In-silico analysis of the Hippo signaling members YAP1 , TEAD1 , AXL , NF2 , CTGF , and CYR61 transcript levels in low-grade GBM and GBM tumor tissues was done by Gene Expression Profiling Interactive Analysis. Gene expression was analyzed by real-time quantitative PCR from human U87, U118, U138, and U251 brain cancer cell lines and in clinically annotated brain tumor cDNA arrays. Transient gene silencing was performed with specific small interfering RNA. Vasculogenic mimicry was assessed using a Cultrex matrix, and three-dimensional capillary-like structures were analyzed with Wimasis. CYR61 and CTGF transcript levels were elevated in GBM tissues and were further induced when in-vitro vasculogenic mimicry was assessed. Silencing of CYR61 and CTGF , or treatment with a small-molecule TEAD inhibitor LM98 derived from flufenamic acid, inhibited vasculogenic mimicry. Silencing of SNAI1 and FOXC2 also altered vasculogenic mimicry and reduced CYR61 / CTGF levels. Pharmacological targeting of the Hippo pathway inhibits in-vitro vasculogenic mimicry. Unraveling the connections between the Hippo pathway and vasculogenic mimicry may pave the way for innovative therapeutic strategies.
胶质母细胞瘤（GBM）是中枢神经系统的一种高度血管生成性恶性肿瘤，对标准抗血管生成疗法具有抗性，部分原因是存在一种名为血管生成拟态的替代血管生成过程。与GBM密切相关的是，Hippo信号通路的失调导致YAP/TEAD以及一些参与治疗抗性的下游效应因子的过表达。关于血管生成拟态和Hippo通路在GBM化疗抗性表型中是否相交，目前知之甚少。本研究旨在调查临床注释的GBM样本中Hippo通路调节因子的表达模式，研究它们在体外与血管生成拟态的关系。此外，它还旨在评估该通路的药物靶向潜力。通过基因表达谱交互式分析对低级别GBM和GBM肿瘤组织中Hippo信号成员YAP1、TEAD1、AXL、NF2、CTGF和CYR61的转录水平进行了计算机分析。通过实时定量PCR对人U87、U118、U138和U251脑癌细胞系以及临床注释的脑肿瘤cDNA阵列中的基因表达进行了分析。使用特异性小干扰RNA进行瞬时基因沉默。使用Cultrex基质评估血管生成拟态，并用Wimasis分析三维毛细血管样结构。CYR61和CTGF的转录水平在GBM组织中升高，在评估体外血管生成拟态时进一步诱导。CYR61和CTGF的沉默，或用源自氟芬那酸的小分子TEAD抑制剂LM98治疗，可抑制血管生成拟态。SNAI1和FOXC2的沉默也改变了血管生成拟态并降低了CYR61/CTGF水平。Hippo通路的药物靶向抑制体外血管生成拟态。揭示Hippo通路与血管生成拟态之间的联系可能为创新治疗策略铺平道路。
