Editors' ChoiceCancer

A case of mistaken identity

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Science Translational Medicine  04 Jan 2017:
Vol. 9, Issue 371, eaal4988
DOI: 10.1126/scitranslmed.aal4988

Abstract

Genuine disseminated tumor cells arise late in the life of a tumor and resemble clones from primary breast cancers or their metastases.

Disseminated tumor cells (DTCs) pose a substantial challenge to curing cancers. Even after removal of the primary tumor, these rare dormant tumor cells, found in distant organs, may serve as potent reservoirs that can drive metastases. Understanding whether DTCs reflect current clones or subclones of the primary tumor (or its metastases), or have evolved from more ancestral ones, is essential for guiding effective therapeutic interventions. Now, Demeulemeester and colleagues describe single-cell analyses that shed new light on the nature of DTCs.

To date, efforts to characterize DTCs have primarily relied on bulk comparative genomic hybridization approaches that have yielded conflicting reports on DTC etiology. Here, the authors applied single-cell DNA sequencing to examine 63 single DTCs from bone marrow aspirates of six nonmetastatic breast cancer patients. By comparing each cell’s DNA sequence with single-nucleotide polymorphism array and whole-exome sequencing data from matched primaries (or a lymph node metastasis), they found that the majority of the cells they had isolated were not bona fide DTCs, despite the use of standard procedures. In fact, after accounting for doublets and controls, only 11 of the remaining 46 proved to be genuine. The remaining 35 were a mixture of normal cells and aberrant ones that might have had an epithelial or hematopoietic origin and correlated in abundance with age. Phylogenetic studies of the real DTCs, meanwhile, demonstrated that they had arisen recently from a clone or subclone of the primary tumor or its lymph node metastasis.

With the confounding genetics of the normal and aberrant nontumor subpopulations removed, this new data suggests that real DTCs are released sequentially and roughly reflect the current primary breast cancer tumor (or its metastases) rather than a much earlier (sub)clone with time to independently evolve and, thus, exhibit different therapeutic properties. Important work that remains to be done includes: (i) examining the generality of these findings in larger cohorts and across tumor types; (ii) identifying better DTC biomarkers; (iii) determining the phenotypic relation between DTCs and matched primary clones; (iv) uncovering the dynamics of DTC generation and turnover; and (v) characterizing the aberrant nontumor cells disguised as DTCs. Nevertheless, the work of Demeulemeester and colleagues optimistically suggests that early breast cancer detection and treatment might be able to prevent DTCs and thus DTC-driven metastases.

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