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Unravelling tumour heterogeneity by single-cell profiling of circulating tumour cells

Nature Reviews Cancer volume 19, pages 553–567 (2019)Cite this article

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Abstract

Single-cell technologies have contributed to unravelling tumour heterogeneity, now considered a hallmark of cancer and one of the main causes of tumour resistance to cancer therapies. Liquid biopsy (LB), defined as the detection and analysis of cells or cell products released by tumours into the blood, offers an appealing minimally invasive approach that allows the characterization and monitoring of tumour heterogeneity in individual patients. Here, we will review and discuss how circulating tumour cell (CTC) analysis at single-cell resolution provides unique insights into tumour heterogeneity that are not revealed by analysis of circulating tumour DNA (ctDNA) derived from LBs. The molecular analysis of CTCs provides complementary information to that of genomic aberrations determined using ctDNA to fully describe many different cellular components (for example, DNA, RNA, proteins and metabolites) that can influence tumour heterogeneity.

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Fig. 1: Biology of tumour blood dissemination: stepwise progression from CTC release to overt metastasis formation.
Fig. 2: Changes in total CTC counts during tumour evolution in patients with cancer.

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Acknowledgements

K.P. received research funding from the Deutsche Forschungsgemeinschaft (DFG) SPP2084 µBone, Deutsche Krebshilfe 'Translationale Onkologie' n° 70112507, EU TRANSCAN-199 Grant PROLIPSY, ERC PoC Grant CTCapture_2.0 n°7544533 H2020 and the EU/IMI consortium CANCER-ID under grant agreement n° 115749, European Union’s Seventh Framework Programme (FP7/2007e2013). L.K. was financially supported by ITMO Cancer 'Plan Cancer 2014-2019' and received funding from Fondation de France.

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  1. Department of Tumour Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

    Laura Keller & Klaus Pantel

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  1. Laura Keller
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Both authors contributed equally to all aspects of the article.

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Correspondence to Klaus Pantel.

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Competing interests

K.P. has ongoing patent applications related to circulating tumour cells, and has received honoraria from Agena, Novartis, Roche and Sanofi and research funding from European Federation of Pharmaceutical Industries and Associations (EFPIA) partners (Angle, Menarini and Servier) of the CANCER-ID programme of the European Union–EFPIA Innovative Medicines Initiative. L.K. declares no competing interests.

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Nature Reviews Cancer thanks N. Aceto, S. Jeffrey and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Blood Profiling Atlas in Cancer (BloodPAC) consortium: https://www.bloodpac.org/

EU Innovative Medicines Initiative (IMI) consortium CANCER-ID: https://www.cancer-id.eu/

European Liquid Biopsy Society (ELBS): http://www.elbs.eu

Glossary

Disseminated tumour cells

(DTCs). A fraction of circulating tumour cells that have extravasated through the endothelium of the blood vessels at distant sites.

Micrometastases

A small collection of tumour cells that have metastasized from the primary tumour in different organs and that are not clinically detectable.

Enriched fractions

Resulting pool of circulating tumour cells in a background of leukocytes after the capture method.

Leptomeningeal metastasis

Corresponds to the spreading of tumour cells to leptomeninges (a thin layer of tissues that protect and cover the brain and the spinal cord).

Cancer-associated fibroblasts

Stromal cells that populate the tumour microenvironment and are involved in cancer progression

CTC-derived xenografts

(CDXs). A model generated from tumorigenic circulating tumour cells in immunocompromised mice.

Parallel progression

A model of progression implying that a metastatic clone leaves the primary tumour early and continues to evolve in parallel to the primary tumour.

Linear progression

A model of progression implying that cancer cells accumulate multiple successive rounds of mutation and selection for invasiveness within the primary tumour before metastasizing.

Convergent evolution

The recurrent tendency of a biological system to independently evolve similar traits arriving at the same solution.

Bisulfite conversion

A technique used to study DNA methylation. Following bisulphite treatment, cytosine is converted into uracil but methylated cytosine is left intact.

Phenotypic switching

The ability of cells in a population to switch states (phenotypes) in response to environmental conditions despite having identical genetic contents.

Optical loss

The attenuation of multiplexed wavelength components passing through the cells.

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Keller, L., Pantel, K. Unravelling tumour heterogeneity by single-cell profiling of circulating tumour cells. Nat Rev Cancer 19, 553–567 (2019). https://doi.org/10.1038/s41568-019-0180-2

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