Glioma stem cells invasive phenotype at optimal stiffness is driven by MGAT5 dependent mechanosensing.
Glioma stem cells invasive phenotype at optimal stiffness is driven by MGAT5 dependent mechanosensing.
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DOI：
10.1186/s13046-021-01925-7
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发表时间：
2021-04-24
期刊：
影响因子：
--
通讯作者：
Bakalara N
中科院分区：
文献类型：
--
作者：
Marhuenda E;Fabre C;Zhang C;Martin-Fernandez M;Iskratsch T;Saleh A;Bauchet L;Cambedouzou J;Hugnot JP;Duffau H;Dennis JW;Cornu D;Bakalara N
胶质母细胞瘤干细胞样细胞（GSCs）通过侵入脑实质，在切除和放疗后残留，肿瘤微环境变得更加僵硬。据报道，GSC侵袭是刚度敏感的，并与改变的N-糖基化模式相关。糖萼厚度调节整联蛋白机械感应，但细节仍然难以捉摸，涉及的糖基化酶是未知的。在这里，我们研究了基质刚度调节，GSC迁移和MGAT 5诱导的N-糖基化之间的关联在纤维状3D背景。为了模拟细胞外基质纤维微环境，我们设计了3D-ex-聚丙烯腈纳米纤维支架（NFS），通过加载多壁碳纳米管（MWCNT）具有可调刚度。将GSC神经球接种在NFS上，允许GSC迁移，并使用CRISPR-Cas9缺失MGAT 5。我们发现GSCs的迁移在166 kPa时达到最大。迁移率与细胞形状、粘着斑（FA）、上皮-间质转化（EMT）蛋白和（β 1，6）分支N-聚糖结合、半乳糖凝集素-3的表达和成熟相关。GSC中MGAT 5的突变抑制N-聚糖（β1-6）分支，抑制迁移对166 kPa NFS的刚度依赖性以及相关的FA和EMT蛋白表达。催化多分支N-聚糖的MGAT 5是刚性诱导的侵袭和GSC机械转导的关键调节剂，支持MGAT 5作为治疗癌症的重要靶标。在线版本包含补充材料，可通过10.1186/s13046-021-01925-7获得。
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. 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. 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. 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. The online version contains supplementary material available at 10.1186/s13046-021-01925-7.
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影响因子：
4
作者：
Bridgewater, Rebecca E.;Norman, Jim C.;Caswell, Patrick T.
通讯作者：
Caswell, Patrick T.
影响因子：
4.6
作者：
Cheng Y;Zhou S;Hu P;Zhao G;Li Y;Zhang X;Han W
通讯作者：
Han W
影响因子：
4.6
作者：
Hu YL;Lu S;Szeto KW;Sun J;Wang Y;Lasheras JC;Chien S
通讯作者：
Chien S
影响因子：
16.6
作者：
Bangasser BL;Shamsan GA;Chan CE;Opoku KN;Tüzel E;Schlichtmann BW;Kasim JA;Fuller BJ;McCullough BR;Rosenfeld SS;Odde DJ
通讯作者：
Odde DJ
影响因子：
13.3
作者：
Iser, Isabele C.;Pereira, Mariana B.;Wink, Marcia R.
通讯作者：
Wink, Marcia R.