Hippo pathway suppression reprograms TNFα-primed glioblastoma extracellular vesicles transcripts cargo to drive mesenchymal stem/stromal cells vasculogenic mimicry.

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Rosalie Zilinski, Angélique Sabaoth Konan, Alain Zgheib, Nicoletta Eliopoulos, Luc H Boudreau, Borhane Annabi
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引用次数: 0

Abstract

Background: Glioblastoma (GBM) secrete extracellular vesicles (EVs) which play a pivotal role in brain tumor progression by mediating intercellular communication within the inflamed tumor microenvironment (TME). EVs' cargo transports biomolecules that promote tumor progression, immune evasion, and resistance to therapies. While Hippo inhibitors play a significant role in mitigating cancer inflammation, their specific impact on EVs cargo remains unknown.

Methods: Human grade IV U87 GBM-derived cells were cultured and EVs isolated from the conditioned media of tumor necrosis factor (TNF)α-primed cells. Total RNA was extracted using TRIzol™, and differential gene expression assessed through gene arrays and validated by RT-qPCR. Protein cell and EVs lysates were used for immunoblotting. 3D mesenchymal stem/stromal cells (MSC) in vitro vasculogenic mimicry (VM) was assessed using Cultrex matrices.

Results: Our study shows that U87 cells are responsive to pro-inflammatory stimulation by TNFα as the phosphorylation status of ERK, IκB, and NFκB increased. Among the Hippo pathway inhibitors tested, VT107 inhibited both the TNFα-induced phosphorylation, induction of the downstream Hippo pathway CYR61, and cargo of secreted EVs as assessed upon gene array screens. Pro-inflammatory genes that were reduced by VT107 in EVs included, among others, COX2, IL6, IL1B, and several members of the CCL, CXCL, and Interleukin/Interleukin receptors family. EVs isolated from VT107-treated TNFα-primed U87 cells had decreased paracrine regulation of MSC in vitro VM.

Conclusions: By inhibiting the Hippo pathway and TNFα-induced pro-inflammatory cargo of GBM-derived EVs, our data support VT107 as a potential candidate to inhibit tumor-promoting processes involved in therapy resistance such as paracrine induction of MSC-mediated VM.

Hippo通路抑制重编程tnf α引发的胶质母细胞瘤细胞外囊泡转录物,以驱动间充质干细胞/基质细胞血管生成模拟。
背景:胶质母细胞瘤(GBM)分泌细胞外囊泡(ev),其通过介导炎症肿瘤微环境(TME)内的细胞间通讯在脑肿瘤进展中起关键作用。电动汽车的货物运输的生物分子,促进肿瘤的进展,免疫逃避和抵抗治疗。虽然Hippo抑制剂在减轻癌症炎症方面发挥着重要作用,但它们对电动汽车货物的具体影响尚不清楚。方法:培养人IV级U87 gbm源性细胞,并从肿瘤坏死因子(TNF)α-引物细胞条件培养基中分离ev。TRIzol™提取总RNA,通过基因阵列评估差异基因表达,RT-qPCR验证差异基因表达。蛋白细胞和ev裂解物用于免疫印迹。使用Cultrex矩阵评估3D间充质干细胞/基质细胞(MSC)体外血管生成模拟(VM)。结果:我们的研究表明,随着ERK、i - κ b和nf - κ b磷酸化水平的升高,U87细胞对TNFα的促炎刺激有反应。在测试的Hippo通路抑制剂中,通过基因阵列筛选评估,VT107抑制tnf α诱导的磷酸化,诱导下游Hippo通路CYR61,以及分泌ev的装载。EVs中被VT107减少的促炎基因包括COX2、IL6、IL1B以及CCL、CXCL和白介素/白介素受体家族的一些成员。从vt107处理的tnf α-引物U87细胞中分离的ev可降低体外VM中MSC的旁分泌调节。结论:通过抑制Hippo通路和tnf α诱导的gbm源性ev的促炎货物,我们的数据支持VT107作为抑制肿瘤促进过程的潜在候选物,这些过程涉及治疗耐药,如msc介导的VM的旁分泌诱导。
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来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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