Circulating tumour cells (CTCs) are the ‘seeds’ of metastasis. Physical interactions with neutrophils have previously been shown to increase the metastatic potential of CTCs by enhancing their adhesive and migratory capacities. Results of a recent study provide new insights into these interactions and identify an additional mechanism by which neutrophils promote metastasis.

This study involved single-cell RNA sequencing or immunostaining and morphological analyses of CTCs isolated from 34 of 70 patients with breast cancer. Most CTCs were solitary or present in homogeneous clusters. However, 3.4% of CTCs were adherent to immune cells, most of a myeloid lineage (75%); ~90% of the myeloid cells were neutrophils with a pro-tumour ‘N2-like’ signature. Similar findings were obtained in five mouse models of breast cancer.

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Simon Bradbrook/Springer Nature Limited

Notably, patients with ≥1 CTC–neutrophil cluster detected had significantly worse progression-free survival than those with ≥5 CTCs detected (P = 0.0001), who are known to have a poor prognosis. Moreover, injection of CTCs derived from CTC–neutrophil clusters into mice resulted in a more rapid onset of overt metastasis than injection of the solitary CTCs. Interestingly, certain recurrent mutations in CTCs (for example, affecting MERTK and TLE1) were associated with CTC–neutrophil clustering and might, therefore, have prognostic relevance.

The gene expression profiles of CTCs from CTC–neutrophil clusters indicated increased proliferative activity but not epithelial–mesenchymal transition or upregulation of stem cell markers. The data also revealed cytokine–receptor pairing between CTCs and neutrophils, implicating neutrophil-derived IL-6 and IL-1β in the enhanced proliferation of CTCs. Moreover, VCAM1 was identified as a potentially targetable protein that mediates CTC–neutrophil interactions.

“Our data suggest that CTC–neutrophil clusters are very efficient seeds of metastases, and preventing their formation in mouse models considerably delays metastasis,” summarizes Nicola Aceto, who led the study. “Preventing the formation of these clusters in patients might also markedly reduce the metastatic potential of cancer cells, and clinical studies are needed to address this point,” he concludes.