Name: a melanoma patient-derived xenograft model
Uploaded: 2019-05-20T14:30:00
Description: Watch this Scientific Journal Video about A Melanoma Patient-Derived Xenograft Model at JoVE.com

作者感谢威斯塔研究所动物设施、显微镜设施、组织技术设施和研究供应中心。这项研究部分由U54(CA224070-01)、SPORE(CA174523)、P01(CA114046-07)、米里亚姆博士和谢尔登·阿德尔森医学研究基金会以及黑色素瘤研究基金会的赠款资助。

以下动物规程遵循威斯塔研究所人道伦理委员会和动物护理指南的准则。
1. 黑色素瘤肿瘤组织收集
<ol><li>通过以下手术或活检方法之一从黑色素瘤患者那里收集肿瘤组织(称为通道 0)。<ol>
<li>对于手术切除组织,在运输储存介质(RPMI 1640 = 0.1% 真菌区 + 0.2% 的温霉素)中,在 4 °C 或冰上保持至少 1 克组织(切除转移和原发性病变)。</li>
		<li>对于外科活检组织,在4°C或冰上的运输储存?...

<ol>
	<li>Garman, B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Genetic+and+Genomic+Characterization+of+462+Melanoma+Patient-Derived+Xenografts,+Tumor+Biopsies,+and+Cell+Lines.">Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines.</a> Cell Reports. 21 (7), 1936-1952 (2017).</li><li>Krepler, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Comprehensive+Patient-Derived+Xenograft+Collection+Representing+the+Heterogeneity+of+Melanoma.">A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma.</a> Cell Reports. 21 (7), 1953-1967 (2017).</li><li>Davies, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mutations+of+the+BRAF+gene+in+human+cancer.">Mutations of the BRAF gene in human cancer.</a> Nature. 417 (6892), 949-954 (2002).</li><li>Paraiso, K. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recovery+of+phospho-ERK+activity+allows+melanoma+cells+to+escape+from+BRAF+inhibitor+therapy.">Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy.</a> British Journal Of Cancer. 102 (12), 1724-1730 (2010).</li><li>Long, G. V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Long-Term+Outcomes+in+Patients+With+BRAF+V600-Mutant+Metastatic+Melanoma+Who+Received+Dabrafenib+Combined+With+Trametinib.">Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib.</a> Journal of Clinical Oncology. 36 (7), 667-673 (2018).</li><li>Hidalgo, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Patient-derived+xenograft+models:+an+emerging+platform+for+translational+cancer+research.">Patient-derived xenograft models: an emerging platform for translational cancer research.</a> Cancer Discovery. 4 (9), 998-1013 (2014).</li><li>Hausser, H. J., Brenner, R. 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H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+of+three+human+small+cell+lung+cancer+models+in+nude+mice.">Development of three human small cell lung cancer models in nude mice.</a> Recent Results In Cancer Research. 97, 77-86 (1985).</li><li>Izumchenko, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Patient-derived+xenografts+effectively+capture+responses+to+oncology+therapy+in+a+heterogeneous+cohort+of+patients+with+solid+tumors.">Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors.</a> Annals of Oncology. 28 (10), 2595-2605 (2017).</li><li>Shi, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Acquired+resistance+and+clonal+evolution+in+melanoma+during+BRAF+inhibitor+therapy.">Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy.</a> Cancer Discovery. 4 (1), 80-93 (2014).</li><li>Monsma, D. 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本文描述了从原发性肿瘤和转移性肿瘤、核心活检和FN中提取患者组织生成黑色素瘤的PDX模型。当直接移植到NSG小鼠中时,肿瘤具有与患者观察到的相似的形态、基因组和生物特性。在只有少量组织可供研究人员使用的情况下,如 FNA 通常发生的情况,PDX 技术允许肿瘤组织扩展以用于 DNA、RNA 和蛋白质表征,以及用于治疗试验,以允许临床前药物发展。
PDX 移植成功的关键是材料调查?...

临床前模型对于转化癌症研究的所有方面都至关重要,包括疾病特征、发现癌症与正常细胞特有的可操作弱点,以及开发利用有效疗法这些弱点,以增加患者的整体生存。在黑色素瘤领域,数以万计的细胞系模型被大量用于药物筛选,仅我们小组就贡献了4,000个细胞系模型(WMXXX系列)。这些细胞系模型来自黑色素瘤患者与各种形式的皮质黑色素瘤(即,腹腔,尿道和表面扩散)和不同的基因型(即,BRAFV600-突变和神经母细胞瘤RAS病毒肿瘤同源性 |国家资源局Q61R-突变体*),它跨越诊所1,2中存在的疾病谱。
毫不含糊地,在黑色素瘤领域最成功的,有针对性的治疗策略已经出现从1)患者肿瘤的基因组表征识别BRAF突变在+50%的黑色素瘤3和2)临床前调查利用黑色素瘤细胞系模型4.BRAF/MEK抑制剂组合是食品和药物管理局(FDA)批准在2014年用于治疗患者的黑色素瘤窝激活BRAFV600E/K突变,并拥有>75%的响应率5。尽管这种初步的疗效,由于多种内在和后天抵抗机制和肿瘤内异质性,几乎在每种情况下都迅速产生抗药性。不幸的是,细胞系模型在塑料容器的二维培养中生长时,不会重述代表性的生物异质性,当研究人员试图进行实验确定时,这掩盖了它们的临床预测潜力。可能有效的治疗与黑色素瘤6的特定形式或基因型的患者。了解如何最好地模拟患者肿瘤内异质性,使研究人员能够更好地开发治疗模式,可以杀死导致失败到当前护理标准疗法的治疗亚人群。
细胞系模型有限的预测价值最大的是它们最初是如何建立的。当患者肿瘤的单细胞悬浮在二维塑料组织培养血管上生长时,肿瘤克隆景观会发生不可逆转的变化,包括增殖和侵入性潜能的变化,消除特定亚种群,遗传信息的改变7。这些黑色素瘤细胞系模型小鼠的异种移植代表了临床前研究在体内平台中最常用的;然而,该策略也遭受复杂的肿瘤异质性临床观察的不良重述。为了克服这一缺陷,人们越来越有兴趣采用更复杂的黑色素瘤临床前模型,包括PDX模型。PDX模型已经使用了30年,在肺癌患者的开创性研究表明,患者对细胞毒性剂的反应与来自同一患者8的PDX模型的反应是一致。最近,在业界和学术中心,人们一直在推动利用 PDX 模型作为临床前研究的首选工具。PDX模型,由于其优越的重述肿瘤异质性在人类患者,更临床上更相关的使用治疗优化工作比细胞系异种移植9。在黑色素瘤中,有巨大的障碍,使治疗管理先进的疾病10。临床相关的PDX模型已被用来模拟临床阻力和确定治疗策略与临床可用的剂,以治疗治疗抗药性肿瘤11,12。简单地说,这里提出的用于生成PDX模型的协议要求将原发性或转移性黑色素瘤(通过活检或手术收集)的新鲜组织皮下植入NOD/scid/IL2受体空(NSG)小鼠。不同群体在方法方法上有不同的变化;然而,一个基本的核心存在13。

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a melanoma patient-derived xenograft model

累积证据表明,在传统二维组织培养容器中生长的黑色素瘤细胞和人类患者体内的分子和生物特性不同。这是由于黑色素瘤细胞的克隆种群的瓶颈选择,这些细胞可以在没有生理条件的情况下在体外茁壮成长。此外,在二维组织培养中对治疗的反应总体上不能忠实地反映对黑色素瘤患者治疗的反应,大多数临床试验未能显示治疗组合的疗效,体 外。虽然将黑色素瘤细胞异种移植到小鼠体内提供了二维组织培养测定中不存在的生理在体内环境,但用于移植的黑色素瘤细胞已经经历了对可能生长在以下的细胞的瓶颈选择建立细胞系时的二维条件。瓶颈造成的不可逆转的改变包括生长和入侵特性的变化,以及特定亚种群的丧失。因此,更好地概括人体体内状况的模型可以更好地预测有效提高转移性黑色素瘤患者整体存活率的治疗策略。患者衍生的异种移植 (PDX) 技术涉及将肿瘤细胞从人类患者直接植入小鼠受体。通过这种方式,肿瘤细胞在体内的生理压力下不断生长,从不经历二维瓶颈,从而保留肿瘤在人类患者体内时存在的分子和生物特性。值得注意的是,从转移器官部位(即大脑)派生的PDX模型显示类似的转移能力,而PDX模型来自治疗天真的患者和获得治疗耐药性的患者(即BRAF/MEK抑制剂治疗)显示类似的敏感性治疗。

黑色素瘤PDX模型的肿瘤组织可以来自各种不同的来源,也可以根据各个模型的生长动态和PDX组织的预期使用进行处理。建立 PDX 模型时,首要任务是有足够的材料供将来使用,DNA 用于表征(图 1)。
一旦有足够的物质被存入,肿瘤组织可以扩大在三种主要方法之一,以增长足够的肿瘤进行正式治疗研究(图2A)。本文介绍的每种方?...

Watch this Scientific Journal Video about A Melanoma Patient-Derived Xenograft Model at JoVE.com

A Melanoma Patient-Derived Xenograft Model (Video) | JoVE

与传统的基于塑料组织培养的检测相比,患者衍生的异种移植 (PDX) 模型更有力地概括黑色素瘤分子和生物特征,并更预测治疗反应。在这里,我们描述了我们用于建立新的 PDX 模型的标准操作协议,以及现有 PDX 模型的特征/实验。

黑色素瘤患者衍生异种移植模型

Accumulating evidence suggests that molecular and biological properties differ in melanoma cells grown in traditional two-dimensional tissue culture ...

PDX彻底改变了癌症实验的临床前研究。我们现在可以在实验室里模仿病人身上发生的事情。现在，我们可以研究如何克服阻力，以及如何，从长远来看，我们可以提高患者的生存。演示程序将是敏晓。首先，将以前收集到的黑色素瘤组织转移到无菌培养皿中。使用手术剪刀、手术刀刀片和钳子，首先尽可能从正常组织中去除正常组织。然后切除肿瘤中央的苍白白色组织识别的坏死组织。然后使用手术刀将初始肿瘤块细分为大约相等的片段，用于手术小鼠植入。如果肿瘤组织太难进行机械分离，使用手术刀尽可能精细地切碎肿瘤块，形成泥浆。将浆料与冷汉克的平衡盐溶液一起转移到50毫升的管中，无需钙和镁离子。在摄氏4度下以220倍g离心4分钟。去除上经剂后，每克肿瘤组织10毫升加热、新鲜消化介质中重新悬浮浆料。将管子放在37摄氏度的水浴中20分钟，每5分钟与一次性移液器进行大力混合。使用高达 50 毫升的 HBSS 洗涤浆料，在 4 摄氏度下以 220 倍 g 离心，4 分钟，然后取出上光。每克肿瘤组织加入五毫升预热 TEG 缓冲液，摇动以轻轻重新悬浮，并将管子在 37 摄氏度下放置两分钟，无需混合。要淬火，请添加至少一个等量的冷染色介质，并在 4 摄氏度下以 220 倍 g 的离心机，在 4 摄氏度下进行 4 分钟。去除上经剂后，每克肿瘤组织加入10毫升染色介质，然后上下移液，重新悬浮颗粒。通过 40 微米细胞滤株过滤它，以获得用于小鼠注射的单细胞悬浮液。要植入手术切除或手术活检组织，首先从NSG下背部剃毛6至8周大麻醉小鼠，留下约1.5厘米至3厘米的区域没有头发。准备肿瘤块，并在培养中将肿瘤浆分成单独的土堆进行手术植入。使用手术刀刀片，在鼠标背面的中心进行大约五毫米长的切口。使用一对钳子，在操作员对面的切口侧皮肤上生活。用剪刀在另一只手，通过轻轻切割皮膜与小剪刀切口，将皮肤从肌肉层分离出来，从而为肿瘤组织创建一个口袋。使用手术刀刀片拿起一个肿瘤夹头，以及一个单独的肿瘤浆组织土堆，并轻轻地将组织放入创建的口袋。然后在口袋里的肿瘤组织土堆上加入100微升的人造细胞外基质。使用两对钳子，拉起两端的切口，使伤口边缘靠近。然后应用一个或两个伤口夹来关闭伤口。皮下注射每公斤镇痛一到五毫克。当完全愈合时，大约七天后，取出伤口夹。每周监测一次小鼠，检查有无可看的肿瘤。一旦肿瘤达到所需的体积，使用手术钳来抬起安乐死小鼠肿瘤附近的皮肤，并使用弯曲的剪刀进行水平切割。使用钝分离技术来调动肿瘤两侧和肿瘤上的皮肤，使肿瘤暴露。使用剪刀和手术刀刀片将肿瘤与筋膜分离。切出肿瘤，并转移到无菌的培养皿。将肿瘤切成小块，从肿瘤中去除坏死组织。为了将肿瘤组织培养成一毫米大小，请将两到三个小肿瘤片切成小于一毫米的肿瘤组织。将所有切碎的组织转移到两毫升低温的卑鄙。加入一毫升冷冻介质，混合好。将小瓶放入干冰上预冷却的异丙醇细胞冷冻容器中，将容器存放在零下80摄氏度的冰柜中过夜，然后将小瓶转移到液氮储存中。要捕捉冷冻组织进行下游检测，将肿瘤组织片放入低温小瓶中，立即将低温恶果放入液氮中，将小瓶存放在零下80摄氏度的冰柜中。在比较肿瘤组织生长的三种不同方法时，利用酶消化对肿瘤细胞的单细胞悬浮利用最成功。除了允许更快速的肿瘤生长，它也足以将一个初始肿瘤扩展到10至20只小鼠，而肿瘤夹头和泥浆法只能扩展到5至10只小鼠。黑色素瘤患者衍生异种移植模型通常反映患者在治疗时表现出的药物敏感性。一种来自黑色素瘤患者的异种移植物，最初对BRAF抑制剂有反应，但最终复发，也表现出对BRAF蛋白抑制的初始敏感性，加上 MEK 激酶抑制剂，但肿瘤最终复发。在为银行准备 PDX 组织时，必须小心，因为这将确保未来 PDX 扩展、治疗试验以及表征的成功。通过PDX材料，单细胞RNA测序、全外显子测序和蛋白质组表征，是我们实验室利用许多方法解剖治疗耐药性的方法之一。PDX技术允许研究人员研究治疗阻力使用肿瘤细胞，更好地重新综述肿瘤生物学在人类患者相对于传统的癌症模型生长在塑料。这一优势允许提供更具预测性的见解。研究人员在处理来自人类患者的肿瘤组织时，应始终小心并使用生物安全二级预防措施。

Research

JoVE Journal

Cancer Research

A Melanoma Patient-Derived Xenograft Model

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies (Video) | JoVE

开发和维护的临床前患者来源的肿瘤异种移植模型为新的抗癌疗法的调查

Patient derived tumor xenograft (PDTX) models provide a necessary platform in facilitating anti-cancer drug development prior to human trials. Human tumor ...

科研

癌症研究

Labeling of Breast Cancer Patient-derived Xenografts with Traceable Reporters for Tumor Growth and Metastasis Studies

Labeling of Breast Cancer Patient-derived Xenografts with Traceable Reporters for Tumor Growth and Metastasis Studies (Video) | JoVE

可追踪记者乳腺癌患者来源的移植瘤贴标肿瘤生长和转移的研究

The use of preclinical models to study tumor biology and response to treatment is central to cancer research. Long-established human cell lines, and many ...

Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma

Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma (Video) | JoVE

人地幔细胞淋巴瘤移植小鼠模型中肿瘤植入的研究

B lymphocytes are key players in immune cell circulation and they mainly home to and reside in lymphoid organs. While normal B cells only proliferate when ...

Establishment of a Primary Culture of Patient-derived Soft Tissue Sarcoma

Establishment of a Primary Culture of Patient-derived Soft Tissue Sarcoma (Video) | JoVE

病人衍生软组织肉瘤原代培养的建立

Soft tissue sarcomas (STS) represent a spectrum of heterogeneous malignancies with a difficult diagnosis, classification, and management. To date, more ...

A 3D Organotypic Melanoma Spheroid Skin Model

A 3D Organotypic Melanoma Spheroid Skin Model (Video) | JoVE

3D 脊髓黑色素瘤球形皮肤模型

Malignant transformation of melanocytes, the pigment cells of human skin, causes formation of melanoma, a highly aggressive cancer with increased ...

Patient-derived Orthotopic Xenograft Models for Human Urothelial Cell Carcinoma and Colorectal Cancer Tumor Growth and Spontaneous Metastasis

Patient-derived Orthotopic Xenograft Models for Human Urothelial Cell Carcinoma and Colorectal Cancer Tumor Growth and Spontaneous Metastasis (Video) | JoVE

患者衍生的人类泌尿细胞癌和结肠直肠癌肿瘤生长和自发转移的正交异种移植模型

Cancer patients have poor prognoses when lymph node (LN) involvement is present in both high-grade urothelial cell carcinoma (HG-UCC) of the bladder and ...

Patient-derived Heterogeneous Xenograft Model of Pancreatic Cancer Using Zebrafish Larvae as Hosts for Comparative Drug Assessment

Patient-derived Heterogeneous Xenograft Model of Pancreatic Cancer Using Zebrafish Larvae as Hosts for Comparative Drug Assessment (Video) | JoVE

患者衍生的胰腺癌异质异种移植模型,使用斑马鱼幼虫作为比较药物评估的宿主

Patient-derived tumor xenograft (PDX) and cell-derived tumor xenograft (CDX) are important techniques for preclinical assessment, medication guidance and ...

Establishment of Gastric Cancer Patient-derived Xenograft Models and Primary Cell Lines

Establishment of Gastric Cancer Patient-derived Xenograft Models and Primary Cell Lines (Video) | JoVE

建立胃癌患者衍生异种移植模型和原细胞系

The use of preclinical models to advance our understanding of tumor biology and investigate the efficacy of therapeutic agents is key to cancer research. ...

Generation of a Liver Orthotopic Human Uveal Melanoma Xenograft Platform in Immunodeficient Mice

Generation of a Liver Orthotopic Human Uveal Melanoma Xenograft Platform in Immunodeficient Mice (Video) | JoVE

在免疫缺陷小鼠中生成肝脏正交人子宫黑色素瘤异种移植平台

In recent decades, subcutaneously implanted patient-derived xenograft tumors or cultured human cell lines have been increasingly recognized as more ...

The Establishment and Utilization of Patient Derived Xenograft Models of Central Nervous System Metastasis

The Establishment and Utilization of Patient Derived Xenograft Models of Central Nervous System Metastasis (Video) | JoVE

患者衍生的中枢神经系统转移异种移植模型的建立与利用

The development of novel therapies for central nervous system (CNS) metastasis has been hindered by the lack of preclinical models that accurately ...