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. 2022 Dec 9;23(2):95–111. doi: 10.1038/s41568-022-00536-4

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Fig. 2 — Clustering of circulating tumour cells (CTCs) may occur exclusively between tumour cells (homotypic CTC clusters), as well as between tumour cells and other cell types (heterotypic CTC clusters). This results in enhanced proliferation and survival in the circulation, enabling superior metastatic proficiency. a, Homotypic clustering of CTCs leads to the creation of typically oligoclonal clusters, kept together by cell adhesion molecules (for example, plakoglobin, claudins and CD44). Expression of these molecules and cluster formation are promoted by hypoxic conditions. CTC clustering triggers epigenetic changes (for example, hypomethylation of binding sites for OCT4, NANOG and SOX2), leading to stem-like cell behaviour, which facilitates metastasis seeding. b, Heterotypic CTC clusters (for example, between tumour cells and neutrophils, cancer-associated fibroblasts or platelets) display increased proliferation, invasion and homing at the metastatic site, as well as protection against immune surveillance. E-cadherin, epithelial cadherin; GPIb-IX-V, glycoprotein Ib–IX–V; GPVI, glycoprotein VI; N-cadherin, neural cadherin; VCAM1, vascular cell adhesion molecule 1.