Single-cell DNA and RNA sequencing reveals the dynamics of intra-tumor heterogeneity in a colorectal cancer model.
Single-cell DNA and RNA sequencing reveals the dynamics of intra-tumor heterogeneity in a colorectal cancer model.
复制标题
DOI：
10.1186/s12915-021-01147-5
复制
发表时间：
2021-09-21
期刊：
影响因子：
5.4
通讯作者：
Kato M
中科院分区：
文献类型：
--
作者：
Ono H;Arai Y;Furukawa E;Narushima D;Matsuura T;Nakamura H;Shiokawa D;Nagai M;Imai T;Mimori K;Okamoto K;Hippo Y;Shibata T;Kato M
肿瘤内异质性（ITH）包括肿瘤中的细胞差异，并与临床结果（如耐药性）相关。然而，很少有人知道的ITH的动态，由于缺乏时间序列分析在单细胞水平。重现癌症发展的小鼠模型可用于受控连续时间采样。我们对200个细胞进行了单细胞外显子组和转录组测序，以研究ITH是如何在小鼠结直肠癌模型中产生的。在该模型中，单个正常肠细胞生长成模仿肠隐窝结构的类器官。在RNAi介导的肿瘤抑制基因APC下调后，将转导的类器官连续移植到小鼠中，以允许暴露于体内微环境，其在癌症发展中发挥相关作用。移植后转录组的ITH增加，而外显子组的ITH减少。类器官培养过程中产生的突变在移植后在体细胞水平上没有很大变化。RNA ITH的增加是由于新的转录亚群的出现。与表达间充质标记基因的初始细胞相反，新的亚群在移植后抑制了这些基因。对来自癌症基因组图谱的结直肠癌数据的分析显示，人类受试者中高比例的转移性病例的表达模式与小鼠中的新细胞亚群相似。这些结果表明，当癌细胞在肿瘤后期具有足够的遗传改变时，转录亚群的诞生可能是适应剧烈微环境变化的关键。这项研究揭示了单细胞RNA和DNA异质性在肿瘤进展中的进化动力学，从而深入了解结直肠癌转移时肿瘤细胞的间充质-上皮转化。在线版本包含补充材料，可通过10.1186/s12915-021-01147-5获得。
Intra-tumor heterogeneity (ITH) encompasses cellular differences in tumors and is related to clinical outcomes such as drug resistance. However, little is known about the dynamics of ITH, owing to the lack of time-series analysis at the single-cell level. Mouse models that recapitulate cancer development are useful for controlled serial time sampling. We performed single-cell exome and transcriptome sequencing of 200 cells to investigate how ITH is generated in a mouse colorectal cancer model. In the model, a single normal intestinal cell is grown into organoids that mimic the intestinal crypt structure. Upon RNAi-mediated downregulation of a tumor suppressor gene APC, the transduced organoids were serially transplanted into mice to allow exposure to in vivo microenvironments, which play relevant roles in cancer development. The ITH of the transcriptome increased after the transplantation, while that of the exome decreased. Mutations generated during organoid culture did not greatly change at the bulk-cell level upon the transplantation. The RNA ITH increase was due to the emergence of new transcriptional subpopulations. In contrast to the initial cells expressing mesenchymal-marker genes, new subpopulations repressed these genes after the transplantation. Analyses of colorectal cancer data from The Cancer Genome Atlas revealed a high proportion of metastatic cases in human subjects with expression patterns similar to the new cell subpopulations in mouse. These results suggest that the birth of transcriptional subpopulations may be a key for adaptation to drastic micro-environmental changes when cancer cells have sufficient genetic alterations at later tumor stages. This study revealed an evolutionary dynamics of single-cell RNA and DNA heterogeneity in tumor progression, giving insights into the mesenchymal-epithelial transformation of tumor cells at metastasis in colorectal cancer. The online version contains supplementary material available at 10.1186/s12915-021-01147-5.
登录
查看更多内容
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1016/j.bbcan.2017.01.003
发表时间：
2017-04
期刊：
Biochimica et biophysica acta. Reviews on cancer
影响因子：
--
作者：
Davis A;Gao R;Navin N
通讯作者：
Navin N
DOI：
10.2165/00066982-200408020-00005
发表时间：
2004-01-01
期刊：
Molecular diagnosis : a journal devoted to the understanding of human disease through the clinical application of molecular biology
影响因子：
--
作者：
Janssens, Nico;Janicot, Michel;Bakker, Annette
通讯作者：
Bakker, Annette
环状核苷酸信号通路在癌症中的作用：预防和治疗的靶标。
影响因子：
5.2
作者：
Fajardo AM;Piazza GA;Tinsley HN
通讯作者：
Tinsley HN