Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns

Yannik Bollen; Ellen Stelloo; Petra van Leenen; Myrna van den Bos; Bas Ponsioen; Bingxin Lu; Markus J van Roosmalen; Ana C F Bolhaqueiro; Christopher Kimberley; Maximilian Mossner; William C H Cross; Nicolle J M Besselink; Bastiaan van der Roest; Sander Boymans; Koen C Oost; Sippe G de Vries; Holger Rehmann; Edwin Cuppen; Susanne M A Lens; Geert J P L Kops; Wigard P Kloosterman; Leon W M M Terstappen; Chris P Barnes; Andrea Sottoriva; Trevor A Graham; Hugo J G Snippert

doi:10.1038/s41588-021-00891-2

Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns

Yannik Bollen, Ellen Stelloo, Petra van Leenen, Myrna van den Bos, Bas Ponsioen, Bingxin Lu, Markus J van Roosmalen, Ana C F Bolhaqueiro, Christopher Kimberley, Maximilian Mossner, William C H Cross, Nicolle J M Besselink, Bastiaan van der Roest, Sander Boymans, Koen C Oost, Sippe G de Vries, Holger Rehmann, Edwin Cuppen, Susanne M A Lens, Geert J P L KopsWigard P Kloosterman, Leon W M M Terstappen, Chris P Barnes, Andrea Sottoriva, Trevor A Graham, Hugo J G Snippert

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

31 Citations (Scopus)

Abstract

Central to tumor evolution is the generation of genetic diversity. However, the extent and patterns by which de novo karyotype alterations emerge and propagate within human tumors are not well understood, especially at single-cell resolution. Here, we present 3D Live-Seq-a protocol that integrates live-cell imaging of tumor organoid outgrowth and whole-genome sequencing of each imaged cell to reconstruct evolving tumor cell karyotypes across consecutive cell generations. Using patient-derived colorectal cancer organoids and fresh tumor biopsies, we demonstrate that karyotype alterations of varying complexity are prevalent and can arise within a few cell generations. Sub-chromosomal acentric fragments were prone to replication and collective missegregation across consecutive cell divisions. In contrast, gross genome-wide karyotype alterations were generated in a single erroneous cell division, providing support that aneuploid tumor genomes can evolve via punctuated evolution. Mapping the temporal dynamics and patterns of karyotype diversification in cancer enables reconstructions of evolutionary paths to malignant fitness.

Original language	English
Pages (from-to)	1187-1195
Number of pages	9
Journal	Nature Genetics
Volume	53
Issue number	8
DOIs	https://doi.org/10.1038/s41588-021-00891-2
Publication status	Published - Aug 2021

Keywords

Cell Proliferation/genetics
Chromatin/genetics
Chromosomes, Human
Colorectal Neoplasms/genetics
Gene Dosage
Humans
Karyotype
Karyotyping
Microscopy, Confocal
Mitosis
Organoids/growth & development
Single-Cell Analysis/methods
Spindle Apparatus/genetics

Access to Document

10.1038/s41588-021-00891-2

Cite this

Bollen, Y., Stelloo, E., van Leenen, P., van den Bos, M., Ponsioen, B., Lu, B., van Roosmalen, M. J., Bolhaqueiro, A. C. F., Kimberley, C., Mossner, M., Cross, W. C. H., Besselink, N. J. M., van der Roest, B., Boymans, S., Oost, K. C., de Vries, S. G., Rehmann, H., Cuppen, E., Lens, S. M. A., ... Snippert, H. J. G. (2021). Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns. Nature Genetics, 53(8), 1187-1195. https://doi.org/10.1038/s41588-021-00891-2

@article{88e20240856b4172b6f06a4464c5de38,

title = "Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns",

abstract = "Central to tumor evolution is the generation of genetic diversity. However, the extent and patterns by which de novo karyotype alterations emerge and propagate within human tumors are not well understood, especially at single-cell resolution. Here, we present 3D Live-Seq-a protocol that integrates live-cell imaging of tumor organoid outgrowth and whole-genome sequencing of each imaged cell to reconstruct evolving tumor cell karyotypes across consecutive cell generations. Using patient-derived colorectal cancer organoids and fresh tumor biopsies, we demonstrate that karyotype alterations of varying complexity are prevalent and can arise within a few cell generations. Sub-chromosomal acentric fragments were prone to replication and collective missegregation across consecutive cell divisions. In contrast, gross genome-wide karyotype alterations were generated in a single erroneous cell division, providing support that aneuploid tumor genomes can evolve via punctuated evolution. Mapping the temporal dynamics and patterns of karyotype diversification in cancer enables reconstructions of evolutionary paths to malignant fitness.",

keywords = "Cell Proliferation/genetics, Chromatin/genetics, Chromosomes, Human, Colorectal Neoplasms/genetics, Gene Dosage, Humans, Karyotype, Karyotyping, Microscopy, Confocal, Mitosis, Organoids/growth & development, Single-Cell Analysis/methods, Spindle Apparatus/genetics",

author = "Yannik Bollen and Ellen Stelloo and {van Leenen}, Petra and {van den Bos}, Myrna and Bas Ponsioen and Bingxin Lu and {van Roosmalen}, {Markus J} and Bolhaqueiro, {Ana C F} and Christopher Kimberley and Maximilian Mossner and Cross, {William C H} and Besselink, {Nicolle J M} and {van der Roest}, Bastiaan and Sander Boymans and Oost, {Koen C} and {de Vries}, {Sippe G} and Holger Rehmann and Edwin Cuppen and Lens, {Susanne M A} and Kops, {Geert J P L} and Kloosterman, {Wigard P} and Terstappen, {Leon W M M} and Barnes, {Chris P} and Andrea Sottoriva and Graham, {Trevor A} and Snippert, {Hugo J G}",

note = "{\textcopyright} 2021. The Author(s).",

year = "2021",

month = aug,

doi = "10.1038/s41588-021-00891-2",

language = "English",

volume = "53",

pages = "1187--1195",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "8",

}

Bollen, Y, Stelloo, E, van Leenen, P, van den Bos, M, Ponsioen, B, Lu, B, van Roosmalen, MJ, Bolhaqueiro, ACF, Kimberley, C, Mossner, M, Cross, WCH, Besselink, NJM, van der Roest, B, Boymans, S, Oost, KC, de Vries, SG, Rehmann, H, Cuppen, E, Lens, SMA, Kops, GJPL, Kloosterman, WP, Terstappen, LWMM, Barnes, CP, Sottoriva, A, Graham, TA & Snippert, HJG 2021, 'Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns', Nature Genetics, vol. 53, no. 8, pp. 1187-1195. https://doi.org/10.1038/s41588-021-00891-2

TY - JOUR

T1 - Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns

AU - Bollen, Yannik

AU - Stelloo, Ellen

AU - van Leenen, Petra

AU - van den Bos, Myrna

AU - Ponsioen, Bas

AU - Lu, Bingxin

AU - van Roosmalen, Markus J

AU - Bolhaqueiro, Ana C F

AU - Kimberley, Christopher

AU - Mossner, Maximilian

AU - Cross, William C H

AU - Besselink, Nicolle J M

AU - van der Roest, Bastiaan

AU - Boymans, Sander

AU - Oost, Koen C

AU - de Vries, Sippe G

AU - Rehmann, Holger

AU - Cuppen, Edwin

AU - Lens, Susanne M A

AU - Kops, Geert J P L

AU - Kloosterman, Wigard P

AU - Terstappen, Leon W M M

AU - Barnes, Chris P

AU - Sottoriva, Andrea

AU - Graham, Trevor A

AU - Snippert, Hugo J G

PY - 2021/8

Y1 - 2021/8

N2 - Central to tumor evolution is the generation of genetic diversity. However, the extent and patterns by which de novo karyotype alterations emerge and propagate within human tumors are not well understood, especially at single-cell resolution. Here, we present 3D Live-Seq-a protocol that integrates live-cell imaging of tumor organoid outgrowth and whole-genome sequencing of each imaged cell to reconstruct evolving tumor cell karyotypes across consecutive cell generations. Using patient-derived colorectal cancer organoids and fresh tumor biopsies, we demonstrate that karyotype alterations of varying complexity are prevalent and can arise within a few cell generations. Sub-chromosomal acentric fragments were prone to replication and collective missegregation across consecutive cell divisions. In contrast, gross genome-wide karyotype alterations were generated in a single erroneous cell division, providing support that aneuploid tumor genomes can evolve via punctuated evolution. Mapping the temporal dynamics and patterns of karyotype diversification in cancer enables reconstructions of evolutionary paths to malignant fitness.

AB - Central to tumor evolution is the generation of genetic diversity. However, the extent and patterns by which de novo karyotype alterations emerge and propagate within human tumors are not well understood, especially at single-cell resolution. Here, we present 3D Live-Seq-a protocol that integrates live-cell imaging of tumor organoid outgrowth and whole-genome sequencing of each imaged cell to reconstruct evolving tumor cell karyotypes across consecutive cell generations. Using patient-derived colorectal cancer organoids and fresh tumor biopsies, we demonstrate that karyotype alterations of varying complexity are prevalent and can arise within a few cell generations. Sub-chromosomal acentric fragments were prone to replication and collective missegregation across consecutive cell divisions. In contrast, gross genome-wide karyotype alterations were generated in a single erroneous cell division, providing support that aneuploid tumor genomes can evolve via punctuated evolution. Mapping the temporal dynamics and patterns of karyotype diversification in cancer enables reconstructions of evolutionary paths to malignant fitness.

KW - Cell Proliferation/genetics

KW - Chromatin/genetics

KW - Chromosomes, Human

KW - Colorectal Neoplasms/genetics

KW - Gene Dosage

KW - Humans

KW - Karyotype

KW - Karyotyping

KW - Microscopy, Confocal

KW - Mitosis

KW - Organoids/growth & development

KW - Single-Cell Analysis/methods

KW - Spindle Apparatus/genetics

U2 - 10.1038/s41588-021-00891-2

DO - 10.1038/s41588-021-00891-2

M3 - Article

C2 - 34211178

SN - 1061-4036

VL - 53

SP - 1187

EP - 1195

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns

Abstract

Keywords

Access to Document

Fingerprint

Cite this