Tracing Clonal Dynamics Reveals that Two- and Three-dimensional Patient-derived Cell Models Capture Tumor Heterogeneity of Clear Cell Renal Cell Carcinoma
Tracing Clonal Dynamics Reveals that Two- and Three-dimensional Patient-derived Cell Models Capture Tumor Heterogeneity of Clear Cell Renal Cell Carcinoma
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DOI：
10.1016/j.euf.2019.06.009
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发表时间：
2021-03-04
影响因子：
5.4
通讯作者：
Moch, Holger
中科院分区：
文献类型：
--
作者：
Bolck, Hella A.;Corro, Claudia;Moch, Holger
背景资料：广泛的DNA测序使人们对个体基因组的多样性及其在透明细胞肾细胞癌（ccRCC）患者中的进化有了前所未有的认识。目的：了解体外患者来源的二维（2D）和三维（3D）ccRCC模型的亚克隆结构和动力学，以确定它们是否反映ccRCC肿瘤间和肿瘤内的异质性。设计、设置和参与者：结果测量和统计分析：我们证实了2D和3D患者来源细胞（PDC）模型与原始肿瘤组织在组织学、生物标志物表达、癌症驱动突变和拷贝数改变方面的一致性。我们通过分析连续传代过程中的克隆动力学来解决患者间和患者内异质性问题。结果和局限性：深入的遗传学表征验证了异质性细胞群体的存在，并揭示了单层和类器官细胞培养物的亚克隆组成与相应的亲本ccRCC之间的高度相似性。克隆动力学在体外细胞连续传代期间是明显的，表明PDC培养物可以提供对ccRCC亚克隆体内进化潜力和治疗敏感性的见解。使用选定的ccRCC靶向治疗药物的概念验证药物分析突出了PDC模型中患者特异性的脆弱性，这些脆弱性无法通过询问市售的细胞系来预测。结论：我们证明PDC模型反映了体外ccRCC的肿瘤间和肿瘤内异质性。基于我们的研究结果，我们设想使用这些模型将促进我们对导致遗传多样性的轨迹及其对个体水平上的治疗后果的理解。患者摘要：在这项研究中，我们开发了来自透明细胞肾细胞癌（ccRCC）的二维和三维患者衍生模型，作为“皿中的小肿瘤”。“我们发现，这些细胞模型保留了人类ccRCC的重要特征，例如深刻的肿瘤异质性，从而突出了它们对癌症研究和精准医学的重要性。(c)2019年欧洲泌尿外科协会。由爱思唯尔公司出版。这是一篇开放获取的文章，获得了CC BY-NC-ND许可证（http：//creativecommons.org/licenses/by-nc-nd/4.0/）。
Background: Extensive DNA sequencing has led to an unprecedented view of the diversity of individual genomes and their evolution among patients with clear cell renal cell carcinoma (ccRCC).Objective: To understand subclonal architecture and dynamics of patient-derived two-dimensional (2D) and three-dimensional (3D) ccRCC models in vitro, in order to determine whether they mirror ccRCC inter-and intratumor heterogeneity.Design, setting, and participants: We have established a comprehensive platform of living renal cancer cell models from ccRCC surgical specimens.Outcome measurements and statistical analysis: We confirmed the concordance of 2D and 3D patient-derived cell (PDC) models with the original tumor tissue in terms of histology, biomarker expression, cancer driver mutations, and copy number alterations. We addressed inter-and intrapatient heterogeneity by analyzing clonal dynamics during serial passaging.Results and limitations: In-depth genetic characterization verified the presence of heterogeneous cell populations, and revealed a high degree of similarity between subclonal compositions of monolayer and organoid cell cultures and the corresponding parental ccRCCs. Clonal dynamics were evident during serial passaging of cells in vitro, suggesting that PDC cultures can offer insights into evolutionary potential and treatment susceptibility of ccRCC subclones in vivo. Proof-of-concept drug profiling using selected ccRCC-targeted therapy agents highlighted patient-specific vulnerabilities in PDC models that could not be anticipated by interrogating commercially available cell lines.Conclusions: We demonstrate that PDC models mirror inter-and intratumor heterogeneity of ccRCC in vitro. Based on our findings, we envision that the use of these models will advance our understanding of the trajectories that cause genetic diversity and their consequences for treatment on an individual level.Patient summary: In this study, we developed two-and three-dimensional patient-derived models from clear cell renal cell carcinoma (ccRCC) as "mini-tumors in a dish." We show that these cell models retain important features of the human ccRCCs such as the profound tumor heterogeneity, thus highlighting their importance for cancer research and precision medicine. (c) 2019 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).