Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer.
Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer.
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DOI：
10.1038/nbt.3837
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发表时间：
2017-06
影响因子：
46.9
通讯作者：
Lowe SW
中科院分区：
文献类型：
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作者：
O'Rourke KP;Loizou E;Livshits G;Schatoff EM;Baslan T;Manchado E;Simon J;Romesser PB;Leach B;Han T;Pauli C;Beltran H;Rubin MA;Dow LE;Lowe SW
结直肠癌 (CRC) 是死亡的主要原因，但缺乏模拟 CRC 进展自然阶段的简便临床前模型。通过结肠类器官的原位移植，我们描述了一种广泛使用的免疫活性结直肠癌模型，该模型在体内概括了整个腺瘤-腺癌-转移轴。移植过程只需不到 5 分钟，在 2/3 小鼠中显示出有效的肿瘤移植，并且可以使用源自 GEMM 的类器官、离体工程的野生型类器官或源自患者的人 CRC 类器官来实现。在该模型中，我们描述了 CRC 从腺癌（6 周）到局部播散性疾病（11-12 周）和自发转移（>20 周）的基因型和时间依赖性进展。此外，我们使用该系统表明，失调的 Wnt 信号传导的丧失对于播散性 CRC 的进展至关重要。因此，我们的方法提供了一种快速灵活的方法来生产用于遗传研究和临床前研究的定制CRC小鼠模型。
Colorectal cancer (CRC) is a leading cause of death, yet facile preclinical models that mimic the natural stages of CRC progression are lacking. Through the orthotopic engraftment of colon organoids we describe a broadly usable immunocompetent CRC model that recapitulates the entire adenoma-adenocarcinoma-metastasis axis in vivo. The engraftment procedure takes less than 5 minutes, shows efficient tumor engraftment in 2/3 mice, and can be achieved using organoids derived from GEMMs, wild type organoids engineered ex vivo, or from patient-derived human CRC organoids. In this model, we describe the genotype and time-dependent progression of CRCs from adenocarcinoma (6 weeks), to local disseminated disease (11–12 weeks) and spontaneous metastasis (>20 weeks). Further, we use the system to show that loss of dysregulated Wnt signaling is critical for the progression of disseminated CRCs. Thus, our approach provides a fast and flexible means to produce tailored CRC mouse models for genetic studies and pre-clinical investigation.