Cell, isoform, and environment factors shape gradients and modulate chemotaxis.
Cell, isoform, and environment factors shape gradients and modulate chemotaxis.
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DOI：
10.1371/journal.pone.0123450
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Linderman JJ
中科院分区：
文献类型：
--
作者：
Chang SL;Cavnar SP;Takayama S;Luker GD;Linderman JJ
趋化因子梯度的形成需要多个过程，包括配体分泌和扩散、受体结合和内化以及配体固定到表面。为了了解这些事件如何动态地形成梯度并影响随后的细胞趋化性，我们建立了一个多尺度混合基于代理的模型，将梯度形成，细胞反应和受体水平信息联系起来。CXCL 12/CXCR 4/CXCR 7信号传导轴与许多癌症的转移高度相关。我们对CXCL 12梯度形成进行建模，因为它受到CXCR 4和CXCR 7的影响，特别关注CXCL 12的三种最高表达的亚型。我们使用来自体外微流体源-汇装置的数据训练和验证了我们的模型。我们的模拟展示了分子水平上的异构体差异如何影响梯度形成和细胞反应。我们确定CXCL 12亚型的配体特性（结合迁移表面和CXCR 4）显着影响迁移，并解释体外趋化性数据的差异。我们扩展了我们的模型来分析肿瘤环境中的CXCL 12梯度形成，并发现CXCL 12-γ亚型的短距离，陡梯度特征在驱动趋化性方面是有效的。我们强调了CXCL 12-γ在癌细胞迁移中的重要性：其对细胞外表面位点和CXCR 4的高效亲和力强烈促进CXCR 4+细胞迁移。CXCL 12-γ也更难抑制，我们预测CXCR 4和CXCR 7的共抑制对于有效阻碍CXCL 12-γ诱导的迁移是必要的。这些发现支持了理解蛋白质亚型差异的日益重要性，特别是它们对癌症治疗的影响。
Chemokine gradient formation requires multiple processes that include ligand secretion and diffusion, receptor binding and internalization, and immobilization of ligand to surfaces. To understand how these events dynamically shape gradients and influence ensuing cell chemotaxis, we built a multi-scale hybrid agent-based model linking gradient formation, cell responses, and receptor-level information. The CXCL12/CXCR4/CXCR7 signaling axis is highly implicated in metastasis of many cancers. We model CXCL12 gradient formation as it is impacted by CXCR4 and CXCR7, with particular focus on the three most highly expressed isoforms of CXCL12. We trained and validated our model using data from an in vitro microfluidic source-sink device. Our simulations demonstrate how isoform differences on the molecular level affect gradient formation and cell responses. We determine that ligand properties specific to CXCL12 isoforms (binding to the migration surface and to CXCR4) significantly impact migration and explain differences in in vitro chemotaxis data. We extend our model to analyze CXCL12 gradient formation in a tumor environment and find that short distance, steep gradients characteristic of the CXCL12-γ isoform are effective at driving chemotaxis. We highlight the importance of CXCL12-γ in cancer cell migration: its high effective affinity for both extracellular surface sites and CXCR4 strongly promote CXCR4+ cell migration. CXCL12-γ is also more difficult to inhibit, and we predict that co-inhibition of CXCR4 and CXCR7 is necessary to effectively hinder CXCL12-γ-induced migration. These findings support the growing importance of understanding differences in protein isoforms, and in particular their implications for cancer treatment.
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DOI：
10.1039/c4ib00015c
发表时间：
2014-05
期刊：
Integrative biology : quantitative biosciences from nano to macro
影响因子：
--
作者：
Cavnar SP;Ray P;Moudgil P;Chang SL;Luker KE;Linderman JJ;Takayama S;Luker GD
通讯作者：
Luker GD
影响因子：
4.3
作者：
Bentley K;Mariggi G;Gerhardt H;Bates PA
通讯作者：
Bates PA
影响因子：
11.2
作者：
Bendall, LJ;Baraz, R;Bradstock, KF
通讯作者：
Bradstock, KF
影响因子：
5.4
作者：
Altenburg, Jeffrey D.;Jin, Qingwen;Alkhatib, Ghalib
通讯作者：
Alkhatib, Ghalib
影响因子：
50.3
作者：
Allinen, M;Beroukhim, R;Polyak, K
通讯作者：
Polyak, K