Tracing the origin of disseminated tumor cells in breast cancer using single-cell sequencing

被引：67

作者：

Demeulemeester, Jonas ^{[1
,2
]}

Kumar, Parveen ^{[2
,3
]}

Moller, Elen K. ^{[4
]}

Nord, Silje ^{[4
]}

Wedge, David C. ^{[5
]}

Peterson, April ^{[6
,7
,8
]}

Mathiesen, Randi R. ^{[4
,9
,10
]}

Fjelldal, Renathe ^{[11
]}

Esteki, Masoud Zamani ^{[2
]}

Theunis, Koen ^{[2
]}

Gallardo, Elia Fernandez ^{[2
]}

Grundstad, A. Jason ^{[6
,7
]}

Borgen, Elin ^{[11
]}

Baumbusch, Lars O. ^{[4
,12
]}

Borresen-Dale, Anne-Lise ^{[4
]}

White, Kevin P. ^{[6
,7
,15
]}

Kristensen, Vessela N. ^{[4
,13
]}

Van Loo, Peter ^{[1
,2
]}

Voet, Thierry ^{[2
,3
]}

Naume, Bjorn ^{[9
,14
]}

机构：

[1] Francis Crick Inst, London, England

[2] KU Leuven Univ Leuven, Dept Human Genet, Leuven, Belgium

[3] Wellcome Trust Sanger Inst, Single Cell Genom Ctr, Hinxton, England

[4] Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway

[5] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton, England

[6] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA

[7] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[8] Univ Wisconsin, Genet Lab, Madison, WI USA

[9] Radiumhosp, Oslo Univ Hosp, Div Surg & Canc Med, Dept Oncol, Oslo, Norway

[10] Akershus Univ Hosp, Dept Oncol, Lorenskog, Norway

[11] Radiumhosp, Oslo Univ Hosp, Dept Pathol, Oslo, Norway

[12] Natl Hosp Norway, Oslo Univ Hosp, Div Paediat & Adolescent Med, Dept Pediat Res, Oslo, Norway

[13] Akershus Univ Hosp, Div Med, Dept Clin Mol Biol EpiGen, Lorenskog, Norway

[14] Univ Oslo, Inst Clin Med, Oslo, Norway

[15] Tempus Labs, Chicago, IL 60654 USA

来源：

GENOME BIOLOGY | 2016年 / 17卷

基金：

英国惠康基金; 比利时弗兰德研究基金会; 欧盟地平线“2020”; 英国医学研究理事会;

关键词：

Disseminated tumor cells; Single-cell sequencing; Intra-tumor genetic heterogeneity; Phylogeny; Metastasis; DETECTABLE CLONAL MOSAICISM; BONE-MARROW; IMMUNOCYTOCHEMICAL DETECTION; MORPHOLOGICAL CATEGORIES; POSITIVE CELLS; EVOLUTION; NUMBER; PERSISTENCE; METASTASIS; MECHANISMS;

D O I：

10.1186/s13059-016-1109-7

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Background: Single-cell micro-metastases of solid tumors often occur in the bone marrow. These disseminated tumor cells (DTCs) may resist therapy and lay dormant or progress to cause overt bone and visceral metastases. The molecular nature of DTCs remains elusive, as well as when and from where in the tumor they originate. Here, we apply single-cell sequencing to identify and trace the origin of DTCs in breast cancer. Results: We sequence the genomes of 63 single cells isolated from six non-metastatic breast cancer patients. By comparing the cells' DNA copy number aberration (CNA) landscapes with those of the primary tumors and lymph node metastasis, we establish that 53% of the single cells morphologically classified as tumor cells are DTCs disseminating from the observed tumor. The remaining cells represent either non-aberrant "normal" cells or "aberrant cells of unknown origin" that have CNA landscapes discordant from the tumor. Further analyses suggest that the prevalence of aberrant cells of unknown origin is age-dependent and that at least a subset is hematopoietic in origin. Evolutionary reconstruction analysis of bulk tumor and DTC genomes enables ordering of CNA events in molecular pseudo-time and traced the origin of the DTCs to either the main tumor clone, primary tumor subclones, or subclones in an axillary lymph node metastasis. Conclusions: Single-cell sequencing of bone marrow epithelial-like cells, in parallel with intra-tumor genetic heterogeneity profiling from bulk DNA, is a powerful approach to identify and study DTCs, yielding insight into metastatic processes. A heterogeneous population of CNA-positive cells is present in the bone marrow of non-metastatic breast cancer patients, only part of which are derived from the observed tumor lineages.

引用

页数：15