Intra-tumour diversification in colorectal cancer at the single-cell level

Sophie F Roerink; Nobuo Sasaki; Henry Lee-Six; Matthew D Young; Ludmil B Alexandrov; Sam Behjati; Thomas J Mitchell; Sebastian Grossmann; Howard Lightfoot; David A Egan; Apollo Pronk; Niels Smakman; Joost van Gorp; Elizabeth Anderson; Stephen J Gamble; Chris Alder; Marc van de Wetering; Peter J Campbell; Michael R Stratton; Hans Clevers

doi:10.1038/s41586-018-0024-3

Intra-tumour diversification in colorectal cancer at the single-cell level

Sophie F Roerink, Nobuo Sasaki, Henry Lee-Six, Matthew D Young, Ludmil B Alexandrov, Sam Behjati, Thomas J Mitchell, Sebastian Grossmann, Howard Lightfoot, David A Egan, Apollo Pronk, Niels Smakman, Joost van Gorp, Elizabeth Anderson, Stephen J Gamble, Chris Alder, Marc van de Wetering, Peter J Campbell, Michael R Stratton, Hans Clevers

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

368 Citations (Scopus)

Abstract

Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells. Most mutations were acquired during the final dominant clonal expansion of the cancer and resulted from mutational processes that are absent from normal colorectal cells. Intra-tumour diversification of DNA methylation and transcriptome states also occurred; these alterations were cell-autonomous, stable, and followed the phylogenetic tree of each cancer. There were marked differences in responses to anticancer drugs between even closely related cells of the same tumour. The results indicate that colorectal cancer cells experience substantial increases in somatic mutation rate compared to normal colorectal cells, and that genetic diversification of each cancer is accompanied by pervasive, stable and inherited differences in the biological states of individual cancer cells.

Original language	English
Pages (from-to)	457-462
Number of pages	6
Journal	Nature
Volume	556
Issue number	7702
DOIs	https://doi.org/10.1038/s41586-018-0024-3
Publication status	Published - Apr 2018

Keywords

Antineoplastic Agents/pharmacology
Cell Proliferation
Clone Cells/drug effects
Colorectal Neoplasms/drug therapy
DNA Methylation
DNA Mutational Analysis
Evolution, Molecular
Gene Expression Regulation, Neoplastic
Humans
Intestinal Mucosa/metabolism
Intestines/cytology
Mutation
Mutation Rate
Organoids/cytology
Single-Cell Analysis
Transcriptome

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10.1038/s41586-018-0024-3

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Roerink, S. F., Sasaki, N., Lee-Six, H., Young, M. D., Alexandrov, L. B., Behjati, S., Mitchell, T. J., Grossmann, S., Lightfoot, H., Egan, D. A., Pronk, A., Smakman, N., van Gorp, J., Anderson, E., Gamble, S. J., Alder, C., van de Wetering, M., Campbell, P. J., Stratton, M. R., & Clevers, H. (2018). Intra-tumour diversification in colorectal cancer at the single-cell level. Nature, 556(7702), 457-462. https://doi.org/10.1038/s41586-018-0024-3

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title = "Intra-tumour diversification in colorectal cancer at the single-cell level",

abstract = "Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells. Most mutations were acquired during the final dominant clonal expansion of the cancer and resulted from mutational processes that are absent from normal colorectal cells. Intra-tumour diversification of DNA methylation and transcriptome states also occurred; these alterations were cell-autonomous, stable, and followed the phylogenetic tree of each cancer. There were marked differences in responses to anticancer drugs between even closely related cells of the same tumour. The results indicate that colorectal cancer cells experience substantial increases in somatic mutation rate compared to normal colorectal cells, and that genetic diversification of each cancer is accompanied by pervasive, stable and inherited differences in the biological states of individual cancer cells.",

keywords = "Antineoplastic Agents/pharmacology, Cell Proliferation, Clone Cells/drug effects, Colorectal Neoplasms/drug therapy, DNA Methylation, DNA Mutational Analysis, Evolution, Molecular, Gene Expression Regulation, Neoplastic, Humans, Intestinal Mucosa/metabolism, Intestines/cytology, Mutation, Mutation Rate, Organoids/cytology, Single-Cell Analysis, Transcriptome",

author = "Roerink, {Sophie F} and Nobuo Sasaki and Henry Lee-Six and Young, {Matthew D} and Alexandrov, {Ludmil B} and Sam Behjati and Mitchell, {Thomas J} and Sebastian Grossmann and Howard Lightfoot and Egan, {David A} and Apollo Pronk and Niels Smakman and {van Gorp}, Joost and Elizabeth Anderson and Gamble, {Stephen J} and Chris Alder and {van de Wetering}, Marc and Campbell, {Peter J} and Stratton, {Michael R} and Hans Clevers",

year = "2018",

month = apr,

doi = "10.1038/s41586-018-0024-3",

language = "English",

volume = "556",

pages = "457--462",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7702",

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Roerink, SF, Sasaki, N, Lee-Six, H, Young, MD, Alexandrov, LB, Behjati, S, Mitchell, TJ, Grossmann, S, Lightfoot, H, Egan, DA, Pronk, A, Smakman, N, van Gorp, J, Anderson, E, Gamble, SJ, Alder, C, van de Wetering, M, Campbell, PJ, Stratton, MR & Clevers, H 2018, 'Intra-tumour diversification in colorectal cancer at the single-cell level', Nature, vol. 556, no. 7702, pp. 457-462. https://doi.org/10.1038/s41586-018-0024-3

TY - JOUR

T1 - Intra-tumour diversification in colorectal cancer at the single-cell level

AU - Roerink, Sophie F

AU - Sasaki, Nobuo

AU - Lee-Six, Henry

AU - Young, Matthew D

AU - Alexandrov, Ludmil B

AU - Behjati, Sam

AU - Mitchell, Thomas J

AU - Grossmann, Sebastian

AU - Lightfoot, Howard

AU - Egan, David A

AU - Pronk, Apollo

AU - Smakman, Niels

AU - van Gorp, Joost

AU - Anderson, Elizabeth

AU - Gamble, Stephen J

AU - Alder, Chris

AU - van de Wetering, Marc

AU - Campbell, Peter J

AU - Stratton, Michael R

AU - Clevers, Hans

PY - 2018/4

Y1 - 2018/4

N2 - Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells. Most mutations were acquired during the final dominant clonal expansion of the cancer and resulted from mutational processes that are absent from normal colorectal cells. Intra-tumour diversification of DNA methylation and transcriptome states also occurred; these alterations were cell-autonomous, stable, and followed the phylogenetic tree of each cancer. There were marked differences in responses to anticancer drugs between even closely related cells of the same tumour. The results indicate that colorectal cancer cells experience substantial increases in somatic mutation rate compared to normal colorectal cells, and that genetic diversification of each cancer is accompanied by pervasive, stable and inherited differences in the biological states of individual cancer cells.

AB - Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells. Most mutations were acquired during the final dominant clonal expansion of the cancer and resulted from mutational processes that are absent from normal colorectal cells. Intra-tumour diversification of DNA methylation and transcriptome states also occurred; these alterations were cell-autonomous, stable, and followed the phylogenetic tree of each cancer. There were marked differences in responses to anticancer drugs between even closely related cells of the same tumour. The results indicate that colorectal cancer cells experience substantial increases in somatic mutation rate compared to normal colorectal cells, and that genetic diversification of each cancer is accompanied by pervasive, stable and inherited differences in the biological states of individual cancer cells.

KW - Antineoplastic Agents/pharmacology

KW - Cell Proliferation

KW - Clone Cells/drug effects

KW - Colorectal Neoplasms/drug therapy

KW - DNA Methylation

KW - DNA Mutational Analysis

KW - Evolution, Molecular

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Intestinal Mucosa/metabolism

KW - Intestines/cytology

KW - Mutation

KW - Mutation Rate

KW - Organoids/cytology

KW - Single-Cell Analysis

KW - Transcriptome

U2 - 10.1038/s41586-018-0024-3

DO - 10.1038/s41586-018-0024-3

M3 - Article

C2 - 29643510

SN - 0028-0836

VL - 556

SP - 457

EP - 462

JO - Nature

JF - Nature

IS - 7702

ER -

Intra-tumour diversification in colorectal cancer at the single-cell level

Abstract

Keywords

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