Numerous studies have evidenced the higher metastatic potential of circulating tumor cell (CTC) clusters in comparison with single CTCs. However, the mechanisms favoring the success of this cooperative dissemination are still “mysterious”. Nichola Aceto´s team is trying to unmask these mechanisms to better understand the metastasis process and determine which other circulating cells are acting as soldiers for the tumoral ones. In this study Szczerba et al. characterized the CTCs clusters present in breast cancer patients and mouse models evidencing that the majority are composed of neutrophils.

Neutrophils are the most abundant type of white blood cell, and are an essential component of the innate immune system. Their role in cancer is controversial since some works have found neutrophils associated with an aggressive cancer evolution but others described the opposite role. Aceto’s group in this study demonstrated an early release of CTCs clusters during breast cancer development, but these early clusters are mainly composed of tumour cells and showed low metastasic efficiency. Contrary, those CTCs accompanied by neutrophils were more efficient for colonization. They characterize by RNAseq these CTC-associated neutrophils and found a gene expression profile linked to pro-tumour N2-like cells.

Besides, taking into account the established association between the mutational load and the presence of myeloid cells in the primary tumour, they explored the genetic profile of CTC-associated neutrophils, finding a higher proportion of C>T substitutions and the presence of high-impact recurrent mutations in genes that promote neutrophil recruitment, such as TLE1. Importantly they also demonstrated that VCAM1 mediates the interaction between CTCs and neutrophils, representing a good target to reduce this dangerous cooperation, where neutrophils are mainly supporting CTCs cell cycle progression in circulation.

This technically complex study evidenced that blood microenvironment is crucial for the CTCs survival and colonization, beyond mere physical protection, and encourage researchers to focus more efforts to better understand the CTCs interactions with other cells to find new therapeutic targets to block the tumour dissemination.

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