Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters
Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters
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DOI：
10.1073/pnas.1508541113
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发表时间：
2016-02-16
影响因子：
11.1
通讯作者：
Ewald, Andrew J.
中科院分区：
文献类型：
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作者：
Cheung, Kevin J.;Padmanaban, Veena;Ewald, Andrew J.
最近的基因组研究挑战了传统的模型，即每个转移都必须来自单个肿瘤细胞，相反，转移可以由多个不同的基因克隆组成。这些有趣的观察提出了一个问题：多克隆转移是如何从原发肿瘤中出现的？在这项研究中，我们使用多色谱系追踪来证明，在常见的乳腺癌小鼠模型中，通过细胞团进行多克隆播种是一种常见的机制，可解释90%的转移。我们在转移的主要阶段直接观察到多种颜色的肿瘤细胞群，包括集体侵袭、局部扩散、血管内血栓、循环中的肿瘤细胞群和微转移。通过实验将肿瘤细胞聚集成簇，可使体外集落形成增加15倍，体内转移形成增加100倍。有趣的是，局部播散的肿瘤细胞群、循环中的肿瘤细胞群和肺微转移瘤经常表达上皮细胞骨架蛋白角蛋白14(K14)。RNA-seq分析显示K14(+)细胞富含桥粒和半桥粒黏附复合体基因，缺失MHC-II类基因。K14表达缺失可减少远处转移，干扰多种转移效应分子的表达，包括Tenascin C(TNC)、Jagged1(Jag1)和EpiRegin(Ereg)。综上所述，我们的发现揭示了K14是转移的关键调节因子，并确立了K14(+)上皮性肿瘤细胞群集体传播以定植远处器官的概念。
Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14(+) cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14(+) epithelial tumor cell clusters disseminate collectively to colonize distant organs.