英国威康桑格研究所M. J. Garnett课题组的一项最新研究提出了肿瘤衍生的类器官生物库绘制癌症基因依赖性图。这一研究成果于2026年8月5日发表在国际顶尖学术期刊《自然》上。

在这里，该课题组人员直接从结直肠癌、食管癌、卵巢癌、胰腺癌和胃癌中提取并鉴定了256个临床注释的肿瘤类器官，作为可再生的、遗传稳定的模型。对每个模型和匹配的患者肿瘤样本进行了广泛的表征，包括全基因组和转录组测序，以及在162个类器官中绘制基因依赖性的全基因组CRISPR-Cas9筛选。综合分析揭示了常见和罕见亚型的基因组和临床依赖性标记，确定了类器官特异性必需基因，并揭示了配对治疗前和治疗后样本中肿瘤进化后的靶向脆弱性。在结直肠癌中，EGFR-RAS-MAPK轴的功能和药理学研究揭示了KRAS变异等位基因的差异作用。这一开放、公开的研究提供了患者源性类器官中基因依赖性的系统图谱，扩大了模型多样性和推进精确肿瘤学所需的机制洞察力。

据悉，癌细胞系仍然是研究和药物发现的基础，但它们不能完全捕获肿瘤的多样性，缺乏相关的患者背景，并且经历了对培养的适应。肿瘤类器官是从患者组织中提取的三维培养物，为细胞系提供了强有力的补充。

附：英文原文

Title: A tumour-derived organoid biobank maps cancer gene dependencies

Author: Herranz-Ors, C., Bhosle, S. G., Beck, A. E., Gilbert, J. G. R., Picco, G., Espejo Valle-Inclan, J., Muyas, F., Valentini, S., Andres, A. E., Ansari, R., Barthorpe, S., Battarbee, G., Beaver, C. M., Brocklesby, S., Cantwell, J., Collins, C. A., Davis, J., Dimitrova, H. G., Doran, J., Efendi, E., Evans, K., Fekry, M., Fowler, T. A., Garcia-Casado, M., Griffiths, J. A. T., Hall, C., Hamer, R., Hardy, C., Hewitson, Z., Hitch, E., Holland, L., Jackson, D. A., Joshi, N., Kavasakali, A., Letchford, L., Lightfoot, H. B., Lingala, H., Mali, I., May, K., Mironenko, T., Morris, J., Pacini, C., Price, S., Robert-Tissot, G., Rogers, H. A., Smith, J. V., Smith, K., Souster, E., Spence, W. J., Thomas, F., Vieira, S. F., Walker, S., Alfonsin, G., Bermingham, H., Coles, H., Ennis, D. P., Freeman, A., Giannone, G., Grehan, N., Griffiths, E. A., Hall, J., Lee, S. L., Leung, E. Y. L., Loreno, C., Millington, C., Mirnezami, A., Nutzinger, B., Orzechowska, K., Pinna, C. M. A., Redmond, A. M., Roberts, K.

Issue&Volume: 2026-08-05

Abstract: Cancer cell lines remain foundational for research and drug discovery, yet they incompletely capture tumour diversity, lack linked patient context, and have undergone adaptation to culture. Tumour organoids are three-dimensional cultures derived from patient tissue that offer a powerful complement to cell lines1. Here we derived and characterized 256 clinically annotated tumour organoids directly from colorectal, oesophageal, ovarian, pancreatic and gastric cancers as renewable, genetically stable models. Extensive characterization of each model and matched patient tumour samples included whole-genome and transcriptome sequencing, and genome-wide CRISPR–Cas9 screens across 162 organoids mapped gene dependencies. Integrative analyses revealed genomic and clinical markers of dependency across common and rare subtypes, identified organoid-specific essential genes, and revealed targetable vulnerabilities following tumour evolution in paired pre- and post-treatment samples. In colorectal cancer, functional and pharmacological interrogation of the EGFR–RAS–MAPK axis uncovered differential effects of KRAS variant alleles. This open, publicly available resource provides a systematic map of gene dependencies in patient-derived organoids, expanding the model diversity and mechanistic insight needed to advance precision oncology.

DOI: 10.1038/s41586-026-10830-y

Source: https://www.nature.com/articles/s41586-026-10830-y