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.
N1 - Publisher Copyright:
© 2021, The Author(s).
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.
UR - http://www.scopus.com/inward/record.url?scp=85109256649&partnerID=8YFLogxK
U2 - 10.1038/s41588-021-00891-2
DO - 10.1038/s41588-021-00891-2
M3 - Article
C2 - 34211178
AN - SCOPUS:85109256649
SN - 1061-4036
VL - 53
SP - 1187
EP - 1195
JO - Nature Genetics
JF - Nature Genetics
IS - 8
ER -