A novel tumor-immune microenvironment (TIME)-on-Chip mimics three dimensional neutrophil-tumor dynamics and neutrophil extracellular traps (NETs)-mediated collective tumor invasion.
A novel tumor-immune microenvironment (TIME)-on-Chip mimics three dimensional neutrophil-tumor dynamics and neutrophil extracellular traps (NETs)-mediated collective tumor invasion.
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DOI：
10.1088/1758-5090/abe1cf
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发表时间：
2021-04-08
期刊：
影响因子：
9
通讯作者：
Chandrasekaran A
中科院分区：
文献类型：
--
作者：
Surendran V;Rutledge D;Colmon R;Chandrasekaran A
中性粒细胞是血液中最丰富的白细胞类型，传统上被认为是感染和炎症的第一免疫应答者。在肿瘤的背景下，嗜中性粒细胞已被证明具有肿瘤促进和肿瘤限制特性。更好地了解中性粒细胞和聚集性肿瘤之间的细胞间动力学可能有助于阐明中性粒细胞参与肿瘤进展的不同方式。为了在体外研究中性粒细胞和生长的肿瘤聚集体的相互作用动力学，在这项工作中，我们设计了一种新型的微流体集成的三维（3D）肿瘤免疫微环境（TIME）芯片设备，我们研究了中性粒细胞对卵巢肿瘤细胞集体3D入侵开始的影响。在本文中，在基于水凝胶的多微孔板上产生和培养并包埋在限定厚度的胶原蛋白基质内的肿瘤球状体与在多孔膜上制造并携带嗜中性粒细胞的3D生物打印使能的微流体系统磁性混合整合。这种设置在体外重建了典型的TIME，以模拟动态中性粒细胞迁移和3D肿瘤侵袭。使用该装置，我们观察到中性粒细胞通过趋化性和产生中性粒细胞胞外陷阱（NETs）对生长的肿瘤球体做出反应。NET的形成刺激了肿瘤细胞从聚集状态到集体侵入周围胶原基质的往复运动，与它们对已知的肿瘤衍生刺激物如转化生长因子和白细胞介素-8的反应相比，这种方式更显着。这种作用被药物诱导的NET形成的抑制逆转，表明癌细胞诱导NET可能是促迁移的肿瘤行为。此外，我们还报告了一个以前未确定的，位置决定的NETosis机制，其中NETs形成的基质细胞外胶原蛋白基质周围的球体，而不是肿瘤接触的NETs，是重要的诱导卵巢肿瘤细胞的集体入侵，从而提供了一个新的抗肿瘤治疗研究的基本原理。
Neutrophils are the most abundant type of leukocytes in the blood, traditionally regarded as the first immune responders to infections and inflammations. In the context of tumors, neutrophils have been shown to possess both tumor-promoting and tumor-limiting properties. A better understanding of the inter-cellular dynamics between the neutrophils and aggregated tumors could possibly shed light on the different modalities of neutrophil involvement in tumor progression. To study in-vitro the interactional dynamics of neutrophils and growing tumor aggregates, in this work, we engineered a novel, microfluidics-integrated, three-dimensional (3D) tumor-immune microenvironment (TIME)-on-Chip device, and we investigated the effect of neutrophils on the inception of collective 3D invasion of ovarian tumor cells. Herein, tumor spheroids generated and cultured on hydrogel based multi-microwell plates, and embedded within collagen matrix of defined thickness, were magnetically hybrid-integrated with a 3D bioprinting enabled microfluidic system fabricated on a porous membrane and carrying neutrophils. This setting recreated a typical TIME in-vitro to model dynamic neutrophil migration and 3D tumor invasion. Using this device, we observed that neutrophils respond to the growing tumor spheroids through both chemotaxis and generation of neutrophil extracellular traps (NETs). The formation of NETs stimulated the reciprocation of tumor cells from their aggregated state to collectively invade into the surrounding collagen matrix, in a manner more significant compared to their response to known tumor-derived stimulants such as transforming growth factor and Interleukin-8. This effect was reversed by drug-induced inhibition of NETs formation, suggesting that induction of NETs by cancer cells could be a pro-migratory tumor behavior. Further, we additionally report a previously unidentified, location-dictated mechanism of NETosis, in which NETs formation within the stromal extracellular collagen matrix around the spheroids, and not tumor-contacted NETs, is important for the induction of collective invasion of the ovarian tumor cells, thus providing a rationale for new anti-tumor therapeutics research.
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影响因子：
5.8
作者：
Gao J;Zhu Y;Nilsson M;Sundfeldt K
通讯作者：
Sundfeldt K
DOI：
10.1126/science.aao4227
发表时间：
2018-09-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Albrengues J;Shields MA;Ng D;Park CG;Ambrico A;Poindexter ME;Upadhyay P;Uyeminami DL;Pommier A;Küttner V;Bružas E;Maiorino L;Bautista C;Carmona EM;Gimotty PA;Fearon DT;Chang K;Lyons SK;Pinkerton KE;Trotman LC;Goldberg MS;Yeh JT;Egeblad M
通讯作者：
Egeblad M
与肿瘤相关的CD66B+中性粒细胞计数是局部宫颈癌复发的独立预后因素。
影响因子：
8.8
作者：
Carus A;Ladekarl M;Hager H;Nedergaard BS;Donskov F
通讯作者：
Donskov F
影响因子：
4.6
作者：
Hallas-Potts, Amelia;Dawson, John C.;Herrington, C. Simon
通讯作者：
Herrington, C. Simon
影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF