<br>间质流增强 3D 微流控芯片中肺癌球体中的 TGF β/Smad 信号传导活性,Lab on a Chip

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间质流增强 3D 微流控芯片中肺癌球体中的 TGF β/Smad 信号传导活性
Lab on a Chip ( IF 6.1 ) Pub Date : 2023-12-04 , DOI: 10.1039/d3lc00886j
Zaid Rahman ₁ , Ankur Deep Bordoloi ₁ , Haifa Rouhana ₁ , Margherita Tavasso ₁ , Gerard van der Zon ₂ , Valeria Garbin ₁ , Peter Ten Dijke ₂ , Pouyan E Boukany ₁

Affiliation

在肿瘤微环境（TME）中，癌细胞使用机械转导途径将生物物理力转化为生化信号。然而，这些途径的潜在机制和功能意义在很大程度上仍不清楚。生物物理力量（如间质流（IF））对机械敏感通路的上调导致各种细胞因子的激活，包括转化生长因子-β （TGF-β）。TGF-β 部分通过 Smad 依赖性信号通路促进癌细胞中的上皮-间充质转化（EMT）。后一个过程与癌细胞运动和侵袭增加有关。目前的研究模型在研究 3D 微环境中生物物理力（例如 IF）和细胞因子（TGF-β）的综合影响的能力有限。我们使用基于 3D 矩阵的微流控平台来证明 IF 对外源性 TGF-β 诱导的 Smad 信号活性上调和间充质标志物波形蛋白在 A549 肺癌球中的表达的增强作用。为了监测这一点，我们使用了稳定整合的基于荧光的报告基因到 A549 癌细胞基因组中。我们的结果表明，IF 增强了嵌入基质微环境中的肺癌球体中外源性 TGF-β 诱导的 Smad 信号活性。此外，我们观察到当暴露于 IF 和 TGF-β 时，A549 球体的细胞运动增加。我们的 3D 微流体模型与实时成像相结合，为研究生理相关 TME 中与侵袭特征相关的癌细胞信号传导和运动提供了强大的工具。

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Interstitial flow potentiates TGF-β/Smad-signaling activity in lung cancer spheroids in a 3D-microfluidic chip

Within the tumor microenvironment (TME), cancer cells use mechanotransduction pathways to convert biophysical forces to biochemical signals. However, the underlying mechanisms and functional significance of these pathways remain largely unclear. The upregulation of mechanosensitive pathways from biophysical forces such as interstitial flow (IF), leads to the activation of various cytokines, including transforming growth factor-β (TGF-β). TGF-β promotes in part via a Smad-dependent signaling pathway the epithelial–mesenchymal transition (EMT) in cancer cells. The latter process is linked to increased cancer cell motility and invasion. Current research models have limited ability to investigate the combined effects of biophysical forces (such as IF) and cytokines (TGF-β) in a 3D microenvironment. We used a 3D-matrix based microfluidic platform to demonstrate the potentiating effect of IF on exogenous TGF-β induced upregulation of the Smad-signaling activity and the expression of mesenchymal marker vimentin in A549 lung cancer spheroids. To monitor this, we used stably integrated fluorescent based reporters into the A549 cancer cell genome. Our results demonstrate that IF enhances exogenous TGF-β induced Smad-signaling activity in lung cancer spheroids embedded in a matrix microenvironment. In addition, we observed an increased cell motility for A549 spheroids when exposed to IF and TGF-β. Our 3D-microfluidic model integrated with real-time imaging provides a powerful tool for investigating cancer cell signaling and motility associated with invasion characteristics in a physiologically relevant TME.

更新日期：2023-12-04

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