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Understanding tumour endothelial cell heterogeneity and function from single-cell omics

Nature Reviews Cancer volume 23, pages 544–564 (2023)Cite this article

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Abstract

Anti-angiogenic therapies (AATs) are used to treat different types of cancers. However, their success is limited owing to insufficient efficacy and resistance. Recently, single-cell omics studies of tumour endothelial cells (TECs) have provided new mechanistic insight. Here, we overview the heterogeneity of human TECs of all tumour types studied to date, at the single-cell level. Notably, most human tumour types contain varying numbers but only a small population of angiogenic TECs, the presumed targets of AATs, possibly contributing to the limited efficacy of and resistance to AATs. In general, TECs are heterogeneous within and across all tumour types, but comparing TEC phenotypes across tumours is currently challenging, owing to the lack of a uniform nomenclature for endothelial cells and consistent single-cell analysis protocols, urgently raising the need for a more consistent approach. Nonetheless, across most tumour types, universal TEC markers (ACKR1, PLVAP and IGFBP3) can be identified. Besides angiogenesis, biological processes such as immunomodulation and extracellular matrix organization are among the most commonly predicted enriched signatures of TECs across different tumour types. Although angiogenesis and extracellular matrix targets have been considered for AAT (without the hoped success), the immunomodulatory properties of TECs have not been fully considered as a novel anticancer therapeutic approach. Therefore, we also discuss progress, limitations, solutions and novel targets for AAT development.

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Fig. 1: Body map of tumour endothelial cells characterized by single-cell RNA-sequencing in different cancer types.
Fig. 2: Common markers and functions of tumour-enriched endothelial cells.
Fig. 3: New technologies to delineate endothelial cell heterogeneity.

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Data availability

Markers and functions of TECs were extracted from the original referenced work. The summarized tables for plotting Fig. 2a and the source code used in this paper and written by Q.Z. are available as Supplementary Information.

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Acknowledgements

The work is supported by the Biomedical Science Discovery Program between the KU Leuven Institution and Khalifa University (Project code: 8434000456).

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Author notes

  1. These authors contributed equally: Mira Mousa, Aisha Shigna Nadukkandy, Lies Franssens, Halima Alnaqbi, Fatima Yousif Alshamsi.

Authors and Affiliations

  1. Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven and Center for Cancer Biology, VIB, Leuven, Belgium

    Qun Zeng, Aisha Shigna Nadukkandy, Lies Franssens & Peter Carmeliet

  2. Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, UAE

    Mira Mousa, Halima Alnaqbi, Habiba Al Safar & Peter Carmeliet

  3. Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Aisha Shigna Nadukkandy & Peter Carmeliet

  4. Department of Biomedical Engineering, Khalifa University of Science and Technology, Abu Dhabi, UAE

    Fatima Yousif Alshamsi & Habiba Al Safar

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Contributions

Q.Z., L.F., M.M., H.A., A.S.N. and F.Y.A. researched data for the article. Q.Z., L.F., M.M., H.A., A.S.N., F.Y.A., H.A.S. and P.C. contributed substantially to discussion of the content and wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Habiba Al Safar or Peter Carmeliet.

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The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Cancer thanks Yihai Cao, Ankur Sharma and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Carmeliet laboratory: https://carmelietlab.sites.vib.be/en/software-tools/

UpSetR software: https://gehlenborglab.shinyapps.io/upsetr/

Supplementary information

Glossary

Angiocrine signalling

The paracrine or juxtacrine signalling between endothelial cells and the neighbouring cells to regulate tissue growth and repair.

Angiogenesis

The formation of new blood vessels from existing ones.

Batch effects

Systematic variations in experimental measurements that are not caused by the biological factors, but rather by technical factors such as differences in experimental conditions, instruments, reagents or equipment.

Chromium single-cell-fixed RNA profiling

A high-throughput single-cell gene expression profiling technique that uses oligonucleotide-conjugated antibodies to capture and barcode individual cells in fixed tissue samples.

Cytometry by time of flight

(CyTOF). A single-cell analysis technique that combines flow cytometry with mass spectrometry and differentiates the metal isotype-labelled antibodies by the time of flight.

Doublet cells

Two or more aggregated cells that are encapsulated into one reaction volume and tagged by the same barcode during a single-cell RNA sequencing experiment.

Duplex RNA in situ hybridization

A technique used to detect and visualize two RNA molecules simultaneously within a single sample.

Fenestral diaphragms

A thin protein barrier anchored in the fenestrae that is found in endothelial cells containing multiple small circular openings.

Gene set variation analysis

A computational method to calculate the gene enrichment score of a pathway in samples.

Genome-scale metabolic models

A mathematical modelling approach that predicts the metabolic network reconstructions, metabolic pathways and metabolite production rates of an organism.

Hierarchical clustering

A computational method to group similar cells and form a hierarchy of clusters.

In silico lineage tracing

A computational method to determine cell lineage and fate of individual cells on the basis of their gene expression profiles and/or epigenetic markers.

Kupffer cells

Specialized liver macrophages involved in maintaining liver homeostasis.

Mural cell

Specialized cells found in the walls of blood vessels, including vascular smooth muscle cells and pericytes.

RNA velocity

A computational method used to predict the direction and speed of cell differentiation by analysing the spliced and unspliced RNA molecules.

Shear stress

The parallel force applied on the endothelial surface of the blood vessel by flowing blood.

Vesicular transcytosis

The transportation of macromolecules from one side of an epithelial or endothelial cell to the other side through vesicles.

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Zeng, Q., Mousa, M., Nadukkandy, A.S. et al. Understanding tumour endothelial cell heterogeneity and function from single-cell omics. Nat Rev Cancer 23, 544–564 (2023). https://doi.org/10.1038/s41568-023-00591-5

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