RT Journal Article
SR Electronic
T1 Single-cell DNA and RNA sequencing reveals the dynamics of intra-tumor heterogeneity in a colorectal cancer model
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 616870
DO 10.1101/616870
A1 Hanako Ono
A1 Yasuhito Arai
A1 Eisaku Furukawa
A1 Daichi Narushima
A1 Tetsuya Matsuura
A1 Hiromi Nakamura
A1 Daisuke Shiokawa
A1 Momoko Nagai
A1 Toshio Imai
A1 Koshi Mimori
A1 Koji Okamoto
A1 Yoshitaka Hippo
A1 Tatsuhiro Shibata
A1 Mamoru Kato
YR 2019
UL http://biorxiv.org/content/early/2019/04/23/616870.abstract
AB 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. 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. 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, suggesting that the birth of transcriptional subpopulations without substantial genetic changes is associated with mesenchymal-epithelial transformation at metastasis. Analyses of colorectal cancer data from The Cancer Genome Atlas, revealed a higher proportion of patients with metastatic tumor among human subjects with expression patterns similar to those of mouse cell subpopulation. This study revealed an evolutionary pattern of single-cell RNA and DNA changes in tumor progression, giving clinical insights into the mesenchymal-epithelial transformation of tumor cells and subclasses of colorectal cancer.Author summary “Intra-tumor heterogeneity (ITH)” is one of the root causes of cancer malignancy, including drug resistance; however, little is known about the time-dependence of ITH. To investigate how ITH is generated, we combined single cell DNA and RNA sequencing technologies with a mouse colorectal cancer model, ideal for time-series analysis. Our results suggested that mouse cancer cells, with sufficient mutations, adapted to the drastic environmental changes of allograft into a mouse. Transcriptional and genetic ITH increased and somewhat decreased, respectively. New transcriptional subpopulations emerged, showing mesenchymal-epithelial transformation. Using human colorectal cancer data, we found a remarkable trend of metastasis in a fraction of human patients whose expression patterns were similar to those of the mouse-cell subpopulations.