血液循环中的肿瘤细胞聚集能力，与肿瘤发生远处器官转移的可能性相关。不过，循环肿瘤细胞聚集的生物学特征及其弱点尚不明确。
2019年1月10日，全球自然科学三大旗舰期刊之一、美国《细胞》正刊发表瑞士巴塞尔大学、瑞士生物信息研究所、苏黎世联邦理工学院的研究报告，分析了乳腺癌患者和小鼠模型单个循环肿瘤细胞和循环肿瘤细胞聚集的全基因组DNA甲基化特征。DNA甲基化属于DNA化学修饰形式之一，能够在不改变DNA序列的前提下，改变基因的结构和功能。
首先，该研究发现循环肿瘤细胞聚集后，细胞分化和细胞增殖相关转录因子（OCT4、NANOG、SOX2、SIN3A）结合部位的DNA甲基化显著减少，伴有胚胎干细胞的恶性生物学表现，与癌症基因组图谱（TCGA）乳腺癌患者无进展生存结局较差显著相关。
随后，该研究对已经获得美国食品药品管理局（FDA）批准的2486种药物进行筛选，最后发现钠钾离子腺苷三磷酸（ATP）水解酶抑制剂（洋地黄类强心药：地高辛、哇巴因）能够将聚集的循环肿瘤细胞解散为单个细胞，恢复关键结合部位的DNA甲基化，从而抑制转移。
哇巴因（东非索马里语：waabaayo，英语：ouabain，发音：wɑ:'bɑ:in 或 wɑ:bein）又译乌本甙、乌巴因、乌巴苷、乌巴箭毒甙、毒毛旋花甙、苦毒毛旋花子苷。
因此，该研究结果表明，循环肿瘤细胞聚集与促进分化和转移的DNA甲基化显著减少相关。利用针对循环肿瘤细胞聚集的钠钾离子泵抑制剂，可抑制乳腺癌转移。
Cell. 2019 Jan 10;176(1-2):98-112.e14.
Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding.
Gkountela S, Castro-Giner F, Szczerba BM, Vetter M, Landin J, Scherrer R, Krol I, Scheidmann MC, Beisel C, Stirnimann CU, Kurzeder C, Heinzelmann-Schwarz V, Rochlitz C, Weber WP, Aceto N.
University Hospital Basel, University of Basel, Basel, Switzerland; SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; ETH Zurich, Basel, Switzerland; ETH Zurich, Zurich, Switzerland.
HIGHLIGHTS
Binding sites for OCT4, SOX2, NANOG, and SIN3A are hypomethylated in CTC clusters
CTC cluster hypomethylation profile correlates with a poor prognosis in breast cancer
Treatment with FDA-approved Na+/K+-ATPase inhibitors dissociates CTC clusters
Dissociation reverts the methylation profile of CTC clusters and suppresses metastasis
The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-associated transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biology. Among 2,486 FDA-approved compounds, we identify Na +/K + ATPase inhibitors that enable the dissociation of CTC clusters into single cells, leading to DNA methylation remodeling at critical sites and metastasis suppression. Thus, our results link CTC clustering to specific changes in DNA methylation that promote stemness and metastasis and point to cluster-targeting compounds to suppress the spread of cancer.
KEYWORDS: RNA sequencing; bisulfite sequencing; circulating tumor cell clusters; circulating tumor cells; drug screen; proliferation-associated transcription factors; single cell sequencing; stemness-associated transcription factors
PMID: 30633912
DOI: 10.1016/j.cell.2018.11.046
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