Integrated in silico and 3D in vitro model of macrophage migration in response to physical and chemical factors in the tumor microenvironment.
Integrated in silico and 3D in vitro model of macrophage migration in response to physical and chemical factors in the tumor microenvironment.
复制标题
集成巨噬细胞响应肿瘤微环境中的物理和化学因素的计算机模拟和 3D 体外模型。
DOI：
10.1093/intbio/zyaa007
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Kamm,AndRogerD
中科院分区：
文献类型：
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作者：
Lee,SharonWeiLing;Seager,RJ;Litvak,Felix;Spill,Fabian;Sieow,JeLin;Leong,PennyHweixian;Kumar,Dillip;Tan,AlrinaShinMin;Wong,SiewCheng;Adriani,Giulia;Zaman,MuhammadHamid;Kamm,AndRogerD
肿瘤微环境（TME）中大量存在巨噬细胞，作为癌细胞侵袭的帮凶。研究已经探索了驱动促肿瘤巨噬细胞功能的生化机制;然而，TME间质流（IF）的作用经常被忽视。因此，我们开发了一种基于三维微流体的肿瘤细胞和巨噬细胞模型，以研究IF如何影响巨噬细胞迁移及其对癌症侵袭的潜在贡献。肿瘤细胞或IF的存在单独增加巨噬细胞迁移的方向性和速度。有趣的是，在肿瘤细胞和IF同时存在的情况下，对巨噬细胞迁移的方向性和速度没有累加效应。此外，我们提出了一种将趋化因子介导的信号传导与机械传感网络结合起来的计算机模型来解释我们的体外观察结果。在我们的模型设计中，我们提出IL-8、CCL 2和β-整联蛋白作为通常调节各种Rho GTPases的关键途径。与此一致，当暴露于饱和浓度的重组IL-8或CCL 2或共同添加亚饱和浓度的两种细胞因子时，体外巨噬细胞迁移保持升高。此外，针对IL-8和/或CCL 2的抗体阻断抑制可由IF恢复的迁移，表明迁移诱导的非依赖于精氨酸的机制。重要的是，我们证明了一个集成的硅和三维体外方法的效用，以帮助设计肿瘤相关的巨噬细胞为基础的免疫策略。
Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor macrophage functions; however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and macrophages to study how IF affects macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased macrophage migration directedness and speed. Interestingly, there was no additive effect on macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present anin silicomodel that couples chemokine-mediated signaling with mechanosensing networks to explain ourin vitroobservations. In our model design, we propose IL-8, CCL2, and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement,in vitromacrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2 or to the co-addition of a sub-saturating concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integratedin silicoand 3Din vitroapproach to aid the design of tumor-associated macrophage-based immunotherapeutic strategies.