Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness.
Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness.
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DOI：
10.1093/noajnl/vdad067
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发表时间：
2023-01
期刊：
影响因子：
--
通讯作者：
Norman, Jim
中科院分区：
文献类型：
--
作者：
Koessinger, Dominik;Novo, David;Koessinger, Anna;Campos, America;Peters, Jasmine;Dutton, Louise;Paschke, Peggy;Zerbst, Desiree;Moore, Madeleine;Mitchell, Louise;Neilson, Matthew;Stevenson, Katrina;Chalmers, Anthony;Tait, Stephen;Birch, Joanna;Norman, Jim
胶质母细胞瘤（GBM）在整个大脑中的浸润导致其在标准治疗（如手术切除、化疗和放疗）后不可避免的复发。需要更深入地了解GBM浸润大脑的机制，以开发控制疾病和减少复发的方法。本研究的目的是发现GBM释放的细胞外囊泡（EV）影响脑微环境以促进浸润的机制，并确定胶质细胞的细胞外基质（ECM）沉积如何改变。CRISPR用于从患者来源的原代和GBM细胞系中删除先前建立的驱动癌侵袭性和EV产生的基因。我们纯化并表征了这些细胞释放的EV，评估了它们在小鼠脑切片中培养促迁移微环境的能力，并评估了星形胶质细胞衍生的ECM对此的贡献。最后，我们确定了CRISPR介导的基因缺失，我们发现它控制GBM细胞和星形胶质细胞之间的EV介导的通讯，当原位注射到CD1裸鼠中时，如何影响GBM浸润。表达p53突变体（p53 R273 H）的GBM细胞与已建立的促侵入功能获得性释放EV，所述EV含有唾液酸粘蛋白、足糖萼蛋白（PODXL），其鼓励星形胶质细胞存款ECM并增加透明质酸（HA）水平。这种富含HA的ECM反过来促进GBM细胞的迁移。因此，CRISPR介导的PODXL缺失在体内对抗GBM的浸润。这项工作描述了EV介导的机制的几个关键组成部分，GBM细胞通过该机制教育星形胶质细胞以支持周围健康脑组织的浸润。
Infiltration of glioblastoma (GBM) throughout the brain leads to its inevitable recurrence following standard-of-care treatments, such as surgical resection, chemo-, and radiotherapy. A deeper understanding of the mechanisms invoked by GBM to infiltrate the brain is needed to develop approaches to contain the disease and reduce recurrence. The aim of this study was to discover mechanisms through which extracellular vesicles (EVs) released by GBM influence the brain microenvironment to facilitate infiltration, and to determine how altered extracellular matrix (ECM) deposition by glial cells might contribute to this. CRISPR was used to delete genes, previously established to drive carcinoma invasiveness and EV production, from patient-derived primary and GBM cell lines. We purified and characterized EVs released by these cells, assessed their capacity to foster pro-migratory microenvironments in mouse brain slices, and evaluated the contribution made by astrocyte-derived ECM to this. Finally, we determined how CRISPR-mediated deletion of genes, which we had found to control EV-mediated communication between GBM cells and astrocytes, influenced GBM infiltration when orthotopically injected into CD1-nude mice. GBM cells expressing a p53 mutant (p53R273H) with established pro-invasive gain-of-function release EVs containing a sialomucin, podocalyxin (PODXL), which encourages astrocytes to deposit ECM with increased levels of hyaluronic acid (HA). This HA-rich ECM, in turn, promotes migration of GBM cells. Consistently, CRISPR-mediated deletion of PODXL opposes infiltration of GBM in vivo. This work describes several key components of an EV-mediated mechanism though which GBM cells educate astrocytes to support infiltration of the surrounding healthy brain tissue.
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神经胶质瘤干细胞衍生外泌体的全身性T细胞免疫抑制是由单核细胞衍生的抑制细胞介导的。
影响因子：
3.7
作者：
Domenis R;Cesselli D;Toffoletto B;Bourkoula E;Caponnetto F;Manini I;Beltrami AP;Ius T;Skrap M;Di Loreto C;Gri G
通讯作者：
Gri G
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
影响因子：
3
作者：
Al-Mayhani, Talal M. Fael;Ball, Siolian L. R.;Watts, Colin
通讯作者：
Watts, Colin
DOI：
10.1016/j.jbc.2021.100549
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Pibuel MA;Poodts D;Díaz M;Hajos SE;Lompardía SL
通讯作者：
Lompardía SL
影响因子：
4
作者：
Jothy, S
通讯作者：
Jothy, S