Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nature. 2020 Dec;588(7837):331-336. doi: 10.1038/s41586-020-2969-2. Epub 2020 Dec 9.
Most deaths from cancer are explained by metastasis, and yet large-scale metastasis research has been impractical owing to the complexity of in vivo models. Here we introduce an in vivo barcoding strategy that is capable of determining the metastatic potential of human cancer cell lines in mouse xenografts at scale. We validated the robustness, scalability and reproducibility of the method and applied it to 500 cell lines spanning 21 types of solid tumour. We created a first-generation metastasis map (MetMap) that reveals organ-specific patterns of metastasis, enabling these patterns to be associated with clinical and genomic features. We demonstrate the utility of MetMap by investigating the molecular basis of breast cancers capable of metastasizing to the brain-a principal cause of death in patients with this type of cancer. Breast cancers capable of metastasizing to the brain showed evidence of altered lipid metabolism. Perturbation of lipid metabolism in these cells curbed brain metastasis development, suggesting a therapeutic strategy to combat the disease and demonstrating the utility of MetMap as a resource to support metastasis research.
大多数癌症死亡是由转移引起的,但由于体内模型的复杂性,大规模的转移研究一直不切实际。在这里,我们介绍了一种体内条形码策略,能够大规模地确定人癌细胞系在小鼠异种移植物中的转移潜力。我们验证了该方法的稳健性、可扩展性和重现性,并将其应用于跨越 21 种实体瘤的 500 个细胞系。我们创建了第一代转移图谱(MetMap),揭示了转移的器官特异性模式,使这些模式能够与临床和基因组特征相关联。我们通过研究能够转移到大脑的乳腺癌的分子基础来证明 MetMap 的实用性,这是这种癌症患者死亡的主要原因。能够转移到大脑的乳腺癌显示出脂质代谢改变的证据。这些细胞中脂质代谢的扰乱抑制了脑转移的发展,这表明了一种治疗该疾病的策略,并证明了 MetMap 作为支持转移研究的资源的实用性。