美国宾夕法尼亚大学Christopher J. Lengner和美国达特茅斯盖塞尔医学院Aaron McKenna等研究团队合作取得最新进展。他们利用转移性癌症的单细胞谱系追踪揭示杂合上皮间质转化 (EMT) 状态的选择。该研究于2021年6月10日发表于国际一流学术期刊《癌细胞》杂志上。
他们介绍了 macsGESTALT，这是一种基于 CRISPR-Cas9 的诱导型谱系记录仪，具有高效的转录和系统发育信息的单细胞捕获能力。将 macsGESTALT 应用于转移性胰腺癌的小鼠模型，他们回复了约 380,000 个 CRISPR 靶位点，并重建了约 28,000 个单细胞在多个转移位点的扩散。他们发现细胞占据EMT状态的连续体。晚期杂合 EMT 状态的转移电位峰值极其罕见，这些状态是从主要是上皮祖先池中积极选择的。
这些晚期杂合 EMT 状态的基因特征可预测人类胰腺癌和肺癌患者的存活率降低，突出了它们与临床疾病进展的相关性。最后，他们观察到 S100 家族基因表达在克隆性不同的转移亚群中的体内传播证据。
据了解，癌症转移的基础仍然知之甚少，部分原因是缺乏高分辨率的探测工具。
附：英文原文
Title: Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states
Author: Kamen P. Simeonov, China N. Byrns, Megan L. Clark, Robert J. Norgard, Beth Martin, Ben Z. Stanger, Jay Shendure, Aaron McKenna, Christopher J. Lengner
Issue&Volume: 2021-06-10
Abstract: The underpinnings of cancer metastasis remain poorly understood, in part due to alack of tools for probing their emergence at high resolution. Here we present macsGESTALT,an inducible CRISPR-Cas9-based lineage recorder with highly efficient single-cellcapture of both transcriptional and phylogenetic information. Applying macsGESTALTto a mouse model of metastatic pancreatic cancer, we recover ～380,000 CRISPR targetsites and reconstruct dissemination of ～28,000 single cells across multiple metastaticsites. We find that cells occupy a continuum of epithelial-to-mesenchymal transition(EMT) states. Metastatic potential peaks in rare, late-hybrid EMT states, which areaggressively selected from a predominately epithelial ancestral pool. The gene signaturesof these late-hybrid EMT states are predictive of reduced survival in both human pancreaticand lung cancer patients, highlighting their relevance to clinical disease progression.Finally, we observe evidence for in vivo propagation of S100 family gene expression across clonally distinct metastatic subpopulations.
DOI: 10.1016/j.ccell.2021.05.005
Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00271-3
Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
官方网址：https://www.cell.com/cancer-cell/home
投稿链接：https://www.editorialmanager.com/cancer-cell/default.aspx
本期文章：《癌细胞》：Online/在线发表
