Ping Yanyan, Xu Chaohan, Xu Liwen, Liao Gaoming, Zhou Yao, Deng Chunyu, Lan Yujia, Yu Fulong, Shi Jian, Wang Li, Xiao Yun, Li Xia
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Harbin, China.
Front Bioeng Biotechnol. 2020 Feb 4;8:12. doi: 10.3389/fbioe.2020.00012. eCollection 2020.
Engineered organoids by sequential introduction of key mutations could help modeling the dynamic cancer progression. However, it remains difficult to determine gene paths which were sufficient to capture cancer behaviors and to broadly explain cancer mechanisms. Here, as a case study of colorectal cancer (CRC), functional and dynamic characterizations of five types of engineered organoids with different mutation combinations of five driver genes (, and ) showed that sequential introductions of all five driver mutations could induce enhanced activation of more hallmark signatures, tending to cancer. Comparative analysis of engineered organoids and corresponding CRC tissues revealed sequential introduction of key mutations could continually shorten the biological distance from engineered organoids to CRC tissues. Nevertheless, there still existed substantial biological gaps between the engineered organoid even with five key mutations and CRC samples. Thus, we proposed an integrative strategy to prioritize gene cascading paths for shrinking biological gaps between engineered organoids and CRC tissues. Our results not only recapitulated the well-known adenoma-carcinoma sequence model (e.g., AKST-organoid with driver mutations in , and ), but also provided potential paths for delineating alternative pathogenesis underlying CRC populations (e.g., A-organoid with mutation). Our strategy also can be applied to both organoids with more mutations and other cancers, which can improve and innovate mechanism across cancer patients for drug design and cancer therapy.
通过依次引入关键突变构建的工程类器官有助于模拟癌症的动态进展。然而，确定足以捕捉癌症行为并广泛解释癌症机制的基因路径仍然很困难。在这里，作为结直肠癌（CRC）的一个案例研究，对具有五种驱动基因（、和）不同突变组合的五种工程类器官进行功能和动态表征表明，依次引入所有五种驱动突变可诱导更多标志性特征的增强激活，趋向于癌症。对工程类器官和相应CRC组织的比较分析表明，依次引入关键突变可不断缩短从工程类器官到CRC组织的生物学距离。然而，即使具有五个关键突变的工程类器官与CRC样本之间仍然存在很大的生物学差距。因此，我们提出了一种综合策略，对基因级联路径进行优先级排序，以缩小工程类器官与CRC组织之间的生物学差距。我们的结果不仅重现了著名的腺瘤-癌序列模型（例如，具有、和驱动突变的AKST类器官），还为描绘CRC群体潜在的替代发病机制提供了潜在路径（例如，具有突变的A类器官）。我们的策略也可应用于具有更多突变的类器官和其他癌症，这可以改进和创新针对癌症患者的药物设计和癌症治疗机制。
