Lawson Devon A, Bhakta Nirav R, Kessenbrock Kai, Prummel Karin D, Yu Ying, Takai Ken, Zhou Alicia, Eyob Henok, Balakrishnan Sanjeev, Wang Chih-Yang, Yaswen Paul, Goga Andrei, Werb Zena
Department of Anatomy, University of California, San Francisco, California 94143, USA.
Department of Medicine, University of California, San Francisco, California 94143, USA.
Nature. 2015 Oct 1;526(7571):131-5. doi: 10.1038/nature15260. Epub 2015 Sep 23.
Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality. Understanding metastasis initiation and progression is critical to developing new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumour cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumours. However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown. Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft models of human breast cancer, we developed a highly sensitive fluorescence-activated cell sorting (FACS)-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low versus high metastatic burden. Metastatic cells from low-burden tissues were distinct owing to their increased expression of stem cell, epithelial-to-mesenchymal transition, pro-survival, and dormancy-associated genes. By contrast, metastatic cells from high-burden tissues were similar to primary tumour cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have considerable tumour-initiating capacity, and can differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with cyclin-dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, in which metastases are initiated by stem-like cells that proliferate and differentiate to produce advanced metastatic disease.
尽管在理解癌症的分子和遗传基础方面取得了重大进展，但转移仍然是90%以上癌症相关死亡的原因。了解转移的起始和进展对于开发治疗和预防转移性疾病的新治疗策略至关重要。流行的理论假设转移是由具有独特特性的罕见肿瘤细胞播种的，这些细胞在启动和传播转移性肿瘤的能力上可能类似于干细胞。然而，人类乳腺癌中转移起始细胞的身份仍然难以捉摸，转移是否具有层次结构也尚不清楚。在这里，我们在单细胞水平上表明，早期转移细胞具有独特的干细胞样基因表达特征。为了从人类乳腺癌患者来源的异种移植模型中识别和分离转移细胞，我们开发了一种基于高灵敏度荧光激活细胞分选（FACS）的检测方法，该方法使我们能够在小鼠外周组织中计数转移细胞。我们比较了低转移负荷组织与高转移负荷组织中转移细胞的基因特征。低负荷组织中的转移细胞因其干细胞、上皮-间质转化、促生存和休眠相关基因的表达增加而不同。相比之下，高负荷组织中的转移细胞与原发性肿瘤细胞相似，原发性肿瘤细胞更具异质性，并且表达更高水平的管腔分化基因。来自低负荷组织的干细胞样转移细胞的移植表明它们具有相当大的肿瘤起始能力，并且可以分化产生管腔样癌细胞。进展到高转移负荷与增殖增加和MYC表达增加有关，细胞周期蛋白依赖性激酶（CDK）抑制剂治疗可减弱这种情况。这些发现支持了转移的层次模型，其中转移由干细胞样细胞起始，这些细胞增殖并分化以产生晚期转移性疾病。
