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最佳硬度下的神经胶质瘤干细胞侵袭表型由 MGAT5 依赖的机械感受驱动。

Glioma stem cells invasive phenotype at optimal stiffness is driven by MGAT5 dependent mechanosensing.

机构信息

Institut des Neurosciences de Montpellier (INM) U-1051, University of Montpellier, 80 rue Augustin Fliche, Hôpital Saint-Eloi, 34091, Montpellier, Cedex 5, France.

School of Engineering and Materials Science, Queen Mary University of London, London, E1 4NS, UK.

出版信息

J Exp Clin Cancer Res. 2021 Apr 24;40(1):139. doi: 10.1186/s13046-021-01925-7.

DOI:10.1186/s13046-021-01925-7
PMID:33894774
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8067292/
Abstract

BACKGROUND

Glioblastomas stem-like cells (GSCs) by invading the brain parenchyma, remains after resection and radiotherapy and the tumoral microenvironment become stiffer. GSC invasion is reported as stiffness sensitive and associated with altered N-glycosylation pattern. Glycocalyx thickness modulates integrins mechanosensing, but details remain elusive and glycosylation enzymes involved are unknown. Here, we studied the association between matrix stiffness modulation, GSC migration and MGAT5 induced N-glycosylation in fibrillar 3D context.

METHOD

To mimic the extracellular matrix fibrillar microenvironments, we designed 3D-ex-polyacrylonitrile nanofibers scaffolds (NFS) with adjustable stiffnesses by loading multiwall carbon nanotubes (MWCNT). GSCs neurosphere were plated on NFSs, allowing GSCs migration and MGAT5 was deleted using CRISPR-Cas9.

RESULTS

We found that migration of GSCs was maximum at 166 kPa. Migration rate was correlated with cell shape, expression and maturation of focal adhesion (FA), Epithelial to Mesenchymal Transition (EMT) proteins and (β1,6) branched N-glycan binding, galectin-3. Mutation of MGAT5 in GSC inhibited N-glycans (β1-6) branching, suppressed the stiffness dependence of migration on 166 kPa NFS as well as the associated FA and EMT protein expression.

CONCLUSION

MGAT5 catalysing multibranched N-glycans is a critical regulators of stiffness induced invasion and GSCs mechanotransduction, underpinning MGAT5 as a serious target to treat cancer.

摘要

背景

神经胶质瘤干细胞（GSCs）通过侵入脑实质，在切除和放疗后仍然存在，并且肿瘤微环境变得更加坚硬。据报道，GSC 侵袭对刚性敏感，并与改变的 N-糖基化模式有关。糖萼厚度调节整合素的机械感觉，但细节仍不清楚，涉及的糖基化酶也未知。在这里，我们研究了基质刚度调节、GSC 迁移和纤维状 3D 环境中 MGAT5 诱导的 N-糖基化之间的关联。

方法

为了模拟细胞外基质纤维状微环境，我们通过加载多壁碳纳米管（MWCNT）设计了具有可调刚度的 3D-ex-聚丙烯腈纳米纤维支架（NFS）。将 GSC 神经球接种在 NFS 上，允许 GSCs 迁移，并使用 CRISPR-Cas9 敲除 MGAT5。

结果

我们发现 GSCs 的迁移率在 166kPa 时最大。迁移率与细胞形状、粘着斑（FA）的表达和成熟、上皮间质转化（EMT）蛋白以及（β1,6）分支 N-聚糖结合、半乳糖凝集素-3有关。GSC 中 MGAT5 的突变抑制了 N-聚糖（β1-6）分支，抑制了在 166kPa NFS 上迁移对刚性的依赖性，以及相关的 FA 和 EMT 蛋白表达。

结论

催化多分支 N-聚糖的 MGAT5 是刚性诱导侵袭和 GSCs 机械转导的关键调节剂，这支持 MGAT5 作为治疗癌症的严重靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/623e/8067292/edf28d91ec25/13046_2021_1925_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/623e/8067292/febb6f56b45f/13046_2021_1925_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/623e/8067292/c0737541a5af/13046_2021_1925_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/623e/8067292/a4272a3f8756/13046_2021_1925_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/623e/8067292/ec03652cf41d/13046_2021_1925_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/623e/8067292/5b127b411f7b/13046_2021_1925_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/623e/8067292/edf28d91ec25/13046_2021_1925_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/623e/8067292/febb6f56b45f/13046_2021_1925_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/623e/8067292/c0737541a5af/13046_2021_1925_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/623e/8067292/a4272a3f8756/13046_2021_1925_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/623e/8067292/ec03652cf41d/13046_2021_1925_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/623e/8067292/5b127b411f7b/13046_2021_1925_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/623e/8067292/edf28d91ec25/13046_2021_1925_Fig6_HTML.jpg

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