AbstractOver the past decade, the emergence of patient-derived tumor organoids (PDTOs) has broadened the repertoire of preclinical models and progressively revolutionized three-dimensional cell culture in oncology. PDTO can be grown from patient tumor samples with high efficiency and faithfully recapitulates the histological and molecular characteristics of the original tumor.

摘要在过去的十年中，患者来源的肿瘤类器官（PDTOs）的出现拓宽了临床前模型的范围，并逐渐彻底改变了肿瘤学中的三维细胞培养。PDTO可以从患者肿瘤样品中高效生长，并忠实地概括了原始肿瘤的组织学和分子特征。

Therefore, PDTOs can serve as invaluable tools in oncology research, and their translation to clinical practice is exciting for the future of precision medicine in oncology. In this review, we provide an overview of methods for establishing PDTOs and their various applications in cancer research, starting with basic research and ending with the identification of new targets and preclinical validation of new anticancer compounds and precision medicine.

因此，PDTOs可以作为肿瘤学研究中的宝贵工具，它们向临床实践的转化对于肿瘤学精准医学的未来是令人兴奋的。在这篇综述中，我们概述了建立PDTO的方法及其在癌症研究中的各种应用，从基础研究开始，到新靶点的鉴定以及新抗癌化合物和精准医学的临床前验证。

Finally, we highlight the challenges associated with the clinical implementation of PDTO, such as its representativeness, success rate, assay speed, and lack of a tumor microenvironment. Technological developments and autologous cocultures of PDTOs and stromal cells are currently ongoing to meet these challenges and optimally exploit the full potential of these models.

最后，我们强调了与PDTO临床实施相关的挑战，例如其代表性，成功率，测定速度以及缺乏肿瘤微环境。目前正在进行PDTOs和基质细胞的技术开发和自体共培养，以应对这些挑战，并最佳地利用这些模型的全部潜力。

The use of PDTOs as standard tools in clinical oncology could lead to a new era of precision oncology in the coming decade..

PDTOs作为临床肿瘤学的标准工具的使用可能会在未来十年带来精确肿瘤学的新时代。。

BackgroundModels in oncology: from 2D to 3D cultureSince the establishment of the first cell line (HeLa) from a cervical cancer sample in 19511, cell lines grown in monolayer cultures have served as tools to advance the understanding of cancer biology and to develop new treatments (Fig. 1). Although their ability to accurately mimic pathology is debated, they are still widely used in research laboratories.

肿瘤学背景模型：从2D到3D培养自19511年从宫颈癌样本中建立第一个细胞系（HeLa）以来，在单层培养物中生长的细胞系已成为促进对癌症生物学理解和开发新疗法的工具（图1）。尽管它们准确模拟病理学的能力存在争议，但它们仍被广泛用于研究实验室。

However, it is acknowledged that their genetic drift over time often prevents them from fully simulating real human tumors2. Their ability to mimic cellular interactions and the various gradients observed in vivo (such as oxygen, nutrients, and metabolites) are also compromised, ultimately affecting important cellular processes such as intracellular signaling pathway activation, adhesion, mechanotransduction, proliferation, and response to anticancer treatments, which does not consistently reflect the physiological reality of cancer tissue.Fig.

然而，人们承认，随着时间的推移，它们的遗传漂移通常会阻止它们完全模拟真实的人类肿瘤2。它们模拟细胞相互作用的能力和体内观察到的各种梯度（如氧气，营养物质和代谢物）也受到损害，最终影响重要的细胞过程，如细胞内信号通路激活，粘附，机械转导，增殖和对抗癌治疗的反应，这并不一致地反映癌症组织的生理现实。图。

1: Timeline of the development of tumor cell models in oncology (created with BioRender.com).Adapted from199.Full size imageIn this context, scientists have sought to maintain or recreate tumor complexity through various three-dimensional (3D) cell culture approaches. The spheroid model was proposed in the early 1970s by radiobiologists3.

1： 肿瘤学中肿瘤细胞模型发展的时间表（由BioRender.com创建）。改编自199年。全尺寸图像在这种情况下，科学家试图通过各种三维（3D）细胞培养方法来维持或重建肿瘤的复杂性。球体模型是由放射生物学家在20世纪70年代初提出的3。

These highly compact spherical structures can reach a size of over 1 mm and are primarily obtained from immortalized cell lines, thus preventing tumor cell adhesion to the culture surface by using various methods (such as rotational culture systems and use of antiadhesive substrates, among other methods) to allow for cell aggregation4.

这些高度紧凑的球形结构可以达到1mm以上的尺寸，主要是从永生化细胞系中获得的，因此通过使用各种方法（例如旋转培养系统和使用抗粘附底物等方法）来防止肿瘤细胞粘附到培养表面）以允许细胞聚集4。

Unfortunately, these cell lines acquire irrelevant mutations over time that do not reflect the biological characteristics of the original tissue.Other 3D tumor .

不幸的是，这些细胞系随着时间的推移获得了不相关的突变，这些突变不能反映原始组织的生物学特征。其他3D肿瘤。

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and L.P. on the PDTO and ORGAPRED core facility was supported by grants from GIS IBiSA, Cancéropôle Nord-Ouest, Ligue contre le Cancer (Calvados’s commitee), the Fondation de l’Avenir, the Fondation ARC pour la Recherche sur le Cancer, the Groupement des Entreprises Françaises dans la Lutte Contre Le Cancer (GEFLUC), the Fonds de Dotation Patrick de Brou de Laurière, La Rochambelle, the Vaincrabe Association, the Lions clubs of Normandy, the Solidarité don d’espoir Association, and the Comprehensive Cancer Center F.

PDTO和Orgapred核心基金的L.P.得到了GIS IBISA、Cancéropôle Nord Ouest、Ligue contre le cancer（卡尔瓦多斯委员会）、Avenir基金会、ARC癌症研究基金会、法国企业抗癌协会（GEFLUC）、Patrick de Brou de Laurière捐赠基金会、La Rochambelle、Vaccinabe协会、诺曼底狮子俱乐部、团结唐·德斯波尔协会的资助，以及综合癌症中心F。

Baclesse. The ORGAPRED, ORGATHEREX, PLATONUS ONE, POLARIS, and EQUIP’INNOV projects were supported by the Normandy County Council and the European Union within the framework of the Operational Programme ERDF/ESF 2014-2020 and by the French state, as part of the planning contract 2015-2020 between the State and the Normandy Region.

巴克斯。ORGAPRED、ORGATHEREX、PLATONUS ONE、POLARIS和EQUIP'INNOV项目得到了诺曼底县议会和欧盟在2014-2020年ERDF/ESF运营计划框架内以及法国政府的支持，这是该州与诺曼底地区2015-2020年规划合同的一部分。

The work of A.V. on the PDTO and OrgaRES core facility (Univ. Lille, CANTHER) were supported by grants from Contrat de Plan Etat-Région CPER Cancer 2015-2020, Cancéropôle Nord-Ouest, the Fondation ARC pour la Recherche Sur Le Cancer, Ligue Contre Le Cancer and GIS IBiSA. The work of G.G. on PDTO and the 3D-Hub-O core facility were supported by research funding from the Cancéropôle Provence-Alpes-Côte d’Azur, the Institut National du Cancer INCa Pré-néo 2019-188, Région Sud and GIS IBiSA.

A.V.在PDTO和ORGARES核心设施（里尔大学，坎瑟）的工作得到了2015-2020年国家区域计划合同CPER癌症、Cancéropôle Nord Ouest、ARC癌症研究基金会、癌症联盟和GIS IBISA的资助。G.G.在PDTO和3D-HUB-O核心设施方面的工作得到了普罗旺斯-阿尔卑斯-蔚蓝海岸Cancéropôle、印加国家癌症研究所2019-188年、Région Sud和GIS IBISA的研究资助。

C.G. and the 3D-Hub-S core facility were supported financially by Cancéropôle Provence-Alpes-Côte.

C、 G.和3D-Hub-S核心设施由Cancéropôle Provence-Alpes-Côte提供财政支持。

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Reprints and permissionsAbout this articleCite this articleThorel, L., Perréard, M., Florent, R. et al. Patient-derived tumor organoids: a new avenue for preclinical research and precision medicine in oncology.

转载和许可本文引用本文Thorel，L.，Perréard，M.，Florent，R。等人。患者来源的肿瘤类器官：肿瘤学临床前研究和精准医学的新途径。

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癌症模型细胞生物学肿瘤生物标志物