Neuroblastoma Invasion Strategies Are Regulated by the Extracellular Matrix.
Neuroblastoma Invasion Strategies Are Regulated by the Extracellular Matrix.
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DOI：
10.3390/cancers13040736
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发表时间：
2021-02-10
期刊：
影响因子：
5.2
通讯作者：
Piskareva O
中科院分区：
文献类型：
--
作者：
Gavin C;Geerts N;Cavanagh B;Haynes M;Reynolds CP;Loessner D;Ewald AJ;Piskareva O
儿科癌症研究一般和神经母细胞瘤，特别是，有最小的临床前转移模型。由于50%的原发性神经母细胞瘤在诊断时已经转移，因此开发模型以了解神经母细胞瘤转移的分子机制是重要的。在这里，我们描述了一种新的患者来源的异种移植物（PDX）和细胞系为基础的类器官模型。我们发现细胞外基质（ECM）的组成影响类器官的生长，活力和局部侵袭。PDX衍生的神经母细胞瘤类器官显示出四种不同的侵袭表型，这些表型依赖于局部微环境，而细胞系在其侵袭策略方面受到更多限制。这些数据支持使用类器官培养来研究神经母细胞瘤侵袭正常组织的生物学和分子基础。神经母细胞瘤是一种发生在儿童交感神经系统的恶性肿瘤。大约一半的患者在诊断时患有转移性疾病，生存率低于50%。我们的理解促进神经母细胞瘤转移的细胞过程将促进适当的实验模型的发展。在这项研究中，我们的目的是探索神经母细胞瘤细胞和类器官的入侵从患者来源的异种移植物（PDX）生长嵌入三维细胞外基质（ECM）水凝胶通过延时显微镜和定量图像分析。我们发现ECM组合物影响类器官的生长、活力和局部侵袭。ECM组合物诱导不同的细胞行为，其中基质胶是局部类器官侵入的优选基质。类器官侵袭是细胞系和PDX依赖性的。我们在PDX衍生的类器官中鉴定了六种不同的表型。相比之下，NB细胞系在其侵袭策略中受到更多表型限制，因为与克隆细胞系簇相比，从细胞系来源的异种移植物中分离的类器官显示出更广泛的表型。添加FBS和bFGF诱导更具侵略性的细胞行为和更广泛的表型。相反，抑制神经母细胞瘤的预后标志物MYCN，导致细胞行为的侵略性降低。PDX类器官、实时成像和本文开发的新型3D培养测定的组合将使阐明控制神经母细胞瘤侵袭的分子机制的进展迅速。
Paediatric cancer research in general and neuroblastoma, in particular, has minimal preclinical models of metastasis. As 50% of primary neuroblastomas have already metastasised at the time of diagnosis, it is important to develop models to understand the molecular mechanisms of neuroblastoma metastasis. Here, we describe a novel patient-derived xenograft (PDX)- and cell line-based organoid model. We found that the extracellular matrix (ECM) composition influenced the growth, viability and local invasion of organoids. PDX-derived neuroblastoma organoids displayed four various invasion phenotypes which were dependent on the local microenvironment, while cell lines were more restricted in their invasion strategies. These data support the use of organoid cultures for studying the biology and molecular basis of neuroblastoma invasion into normal tissues. Neuroblastoma is a paediatric malignancy of the developing sympathetic nervous system. About half of the patients have metastatic disease at the time of diagnosis and a survival rate of less than 50%. Our understanding of the cellular processes promoting neuroblastoma metastases will be facilitated by the development of appropriate experimental models. In this study, we aimed to explore the invasion of neuroblastoma cells and organoids from patient-derived xenografts (PDXs) grown embedded in 3D extracellular matrix (ECM) hydrogels by time-lapse microscopy and quantitative image analysis. We found that the ECM composition influenced the growth, viability and local invasion of organoids. The ECM compositions induced distinct cell behaviours, with Matrigel being the preferred substratum for local organoid invasion. Organoid invasion was cell line- and PDX-dependent. We identified six distinct phenotypes in PDX-derived organoids. In contrast, NB cell lines were more phenotypically restricted in their invasion strategies, as organoids isolated from cell line-derived xenografts displayed a broader range of phenotypes compared to clonal cell line clusters. The addition of FBS and bFGF induced more aggressive cell behaviour and a broader range of phenotypes. In contrast, the repression of the prognostic neuroblastoma marker, MYCN, resulted in less aggressive cell behaviour. The combination of PDX organoids, real-time imaging and the novel 3D culture assays developed herein will enable rapid progress in elucidating the molecular mechanisms that control neuroblastoma invasion.
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影响因子：
4.6
作者：
Elisha Y;Kalchenko V;Kuznetsov Y;Geiger B
通讯作者：
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影响因子：
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作者：
Huang M;Weiss WA
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影响因子：
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作者：
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粘着斑蛋白在三维细胞运动中的独特作用。
影响因子：
21.3
作者：
Fraley, Stephanie I.;Feng, Yunfeng;Krishnamurthy, Ranjini;Kim, Dong-Hwee;Celedon, Alfredo;Longmore, Gregory D.;Wirtz, Denis
通讯作者：
Wirtz, Denis