A Human Organotypic Microfluidic Tumor Model Permits Investigation of the Interplay between Patient-Derived Fibroblasts and Breast Cancer Cells.
A Human Organotypic Microfluidic Tumor Model Permits Investigation of the Interplay between Patient-Derived Fibroblasts and Breast Cancer Cells.
复制标题
人类器官型微流体肿瘤模型可以研究患者来源的成纤维细胞和乳腺癌细胞之间的相互作用。
DOI：
10.1158/0008-5472.can-18-2293
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发表时间：
2019
期刊：
影响因子：
11.2
通讯作者：
Nikkhah,Mehdi
中科院分区：
文献类型：
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作者：
Truong,DanhD;Kratz,Alexander;Park,JinG;Barrientos,EricS;Saini,Harpinder;Nguyen,Toan;Pockaj,Barbara;Mouneimne,Ghassan;LaBaer,Joshua;Nikkhah,Mehdi
肿瘤-间质相互作用显著影响癌细胞转移和疾病进展。这些相互作用部分由肿瘤和间质成纤维细胞之间的串扰组成，但控制癌症侵袭的串扰中的关键分子机制仍不清楚。在这里，我们调整了我们以前开发的微流体装置作为3Din vitroorganotypic模型，通过模拟芯片上肿瘤微环境的空间组织来机械地研究肿瘤-基质相互作用。我们分别在3D肿瘤和间质区域共培养乳腺癌和患者来源的成纤维细胞，并将功能评估（包括癌细胞迁移）与转录组分析相结合，以揭示肿瘤-间质串扰对侵袭的分子影响。这导致观察到癌症相关成纤维细胞（CAF）通过诱导乳腺癌细胞中新型感兴趣基因非转移性糖蛋白B（GPNMB）的表达来增强3D侵袭，从而导致迁移速度加快。重要的是，GPNMB的敲低减弱了CAF对增强的癌症侵袭的影响。总体而言，这些结果表明，我们的模型重演患者特异性肿瘤微环境的能力，以调查肿瘤间质相互作用的细胞和分子后果。SignificanceAn器官型模型的肿瘤间质相互作用的微流控芯片揭示，CAFs促进乳腺癌细胞中的GPNMB的表达增强入侵。
Tumor–stroma interactions significantly influence cancer cell metastasis and disease progression. These interactions are partly comprised of the cross-talk between tumor and stromal fibroblasts, but the key molecular mechanisms within the cross-talk that govern cancer invasion are still unclear. Here, we adapted our previously developed microfluidic device as a 3Din vitroorganotypic model to mechanistically study tumor–stroma interactions by mimicking the spatial organization of the tumor microenvironment on a chip. We cocultured breast cancer and patient-derived fibroblast cells in 3D tumor and stroma regions, respectively, and combined functional assessments, including cancer cell migration, with transcriptome profiling to unveil the molecular influence of tumor–stroma cross-talk on invasion. This led to the observation that cancer-associated fibroblasts (CAF) enhanced invasion in 3D by inducing expression of a novel gene of interest, glycoprotein nonmetastatic B (GPNMB), in breast cancer cells, resulting in increased migration speed. Importantly, knockdown of GPNMB blunted the influence of CAF on enhanced cancer invasion. Overall, these results demonstrate the ability of our model to recapitulate patient-specific tumor microenvironments to investigate the cellular and molecular consequences of tumor–stroma interactions.SignificanceAn organotypic model of tumor–stroma interactions on a microfluidic chip reveals that CAFs promote invasion by enhancing expression of GPNMB in breast cancer cells.