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Single-cell DNA and RNA sequencing reveals the dynamics of intra-tumor heterogeneity in a colorectal cancer model

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Version 4 2021-08-25, 13:32
Version 3 2021-08-11, 03:16
Version 2 2021-08-10, 08:21
Version 1 2021-08-06, 00:07
posted on 2021-08-25, 13:32 authored by Hanako Ono, Yasuhito Arai, Eisaku FurukawaEisaku Furukawa, Daichi Narushima, Tetsuya Matsuura, Hiromi Nakamura, Daisuke Shiokawa, Momoko NAGAIMomoko NAGAI, Toshio Imai, Koshi Mimori, Koji Okamoto, Yoshitaka Hippo, Tatsuhiro Shibata, Mamoru KatoMamoru Kato
Background: 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.
Results: We performed single-cell exome and transcriptome sequencing of 200 cells
and investigated how ITH is generated from one single cell in a mouse colorectal
cancer model. The ITH of the transcriptome increased after transplantation from
cultured organoids, while that of the exome decreased. Mutations generated in the
culture did not greatly change at the transplantation at the bulk-cell level. 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 at 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.
Conclusions: 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.


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