A Colorectal Tumor Organoid Library Demonstrates Progressive Loss of Niche Factor Requirements during Tumorigenesis
A Colorectal Tumor Organoid Library Demonstrates Progressive Loss of Niche Factor Requirements during Tumorigenesis
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DOI：
10.1016/j.stem.2016.04.003
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发表时间：
2016-06-02
期刊：
影响因子：
23.9
通讯作者：
Sato, Toshiro
中科院分区：
文献类型：
--
作者：
Fujii, Masayuki;Shimokawa, Mariko;Sato, Toshiro
结直肠肿瘤是一种异质性疾病，患者的临床表现和预后各不相同。为了建立一个涵盖这种多样性的平台，我们从一系列组织学亚型和临床阶段（包括罕见亚型）中生成了55个结直肠肿瘤类器官系。根据基因表达特征对每个品系进行定义，并根据生态位因子要求对类器官培养进行优化。在体外和异种移植中，类器官复制了其亲代肿瘤的组织病理学等级和分化能力。值得注意的是，我们发现不依赖于小生境的生长主要与反映多种突变积累的腺瘤-癌转变相关。对于具有相似遗传谱和生态位因子要求的原发和转移性类器官配对，转移性类器官表现出更高的转移能力。这些观察结果强调了在单个患者水平上进行基因型-表型分析的重要性，以及我们的资源在深入了解结直肠肿瘤发生和以患者为中心的治疗开发方面的价值。
Colorectal tumor is a heterogeneous disease, with varying clinical presentation and prognosis in patients. To establish a platform encompassing this diversity, we generated 55 colorectal tumor organoid lines from a range of histological subtypes and clinical stages, including rare subtypes. Each line was defined by gene expression signatures and optimized for organoid culture according to niche factor requirements. In vitro and in xenografts, the organoids reproduced the histopathological grade and differentiation capacity of their parental tumors. Notably, we found that niche-independent growth is predominantly associated with the adenoma-carcinoma transition reflecting accumulation of multiple mutations. For matched pairs of primary and metastatic organoids, which had similar genetic profiles and niche factor requirements, the metastasis-derived organoids exhibited higher metastatic capacity. These observations underscore the importance of genotype-phenotype analyses at a single-patient level and the value of our resource to provide insights into colorectal tumorigenesis and patient-centered therapeutic development.