TY - JOUR
T1 - Tracing the origin of disseminated tumor cells in breast cancer using single-cell sequencing
AU - Demeulemeester, Jonas
AU - Kumar, Parveen
AU - Møller, Elen K.
AU - Nord, Silje
AU - Wedge, David C.
AU - Peterson, April
AU - Mathiesen, Randi R.
AU - Fjelldal, Renathe
AU - Zamani Esteki, Masoud
AU - Theunis, Koen
AU - Fernandez Gallardo, Elia
AU - Grundstad, A. Jason
AU - Borgen, Elin
AU - Baumbusch, Lars O.
AU - Børresen-Dale, Anne Lise
AU - White, Kevin P.
AU - Kristensen, Vessela N.
AU - Van Loo, Peter
AU - Voet, Thierry
AU - Naume, Bjørn
N1 - Publisher Copyright:
© 2016 The Author(s).
PY - 2016/12/9
Y1 - 2016/12/9
N2 - 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-aberrantnorma cells oraberrant cells of unknown origi 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.
AB - 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-aberrantnorma cells oraberrant cells of unknown origi 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.
KW - Disseminated tumor cells
KW - Intra-tumor genetic heterogeneity
KW - Metastasis
KW - Phylogeny
KW - Single-cell sequencing
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U2 - 10.1186/s13059-016-1109-7
DO - 10.1186/s13059-016-1109-7
M3 - Review article
C2 - 27931250
AN - SCOPUS:85002640264
SN - 1474-7596
VL - 17
JO - Genome biology
JF - Genome biology
IS - 1
M1 - 250
ER -