Abstract
IntroductionTumour metastasis is the major cause for mortality in cancer patients. Novel strategies to prevent metastatic dissemination are therefore needed to provide curative treatment options for patients with metastatic cancer. Therapeutic targeting of circulating tumour cells (CTCs) may offer new strategies for the prevention or reduction of metastasis.One common aspect of metastasis is dynamic de- and repolarisation of tumour cells throughout the metastatic cascade. Whether tumour cells are polarised in circulation and during other phases of detachment and if such polarisation plays a role in metastatic seeding has not been investigated previously. In this comprehensive study, we have identified and characterised a novel type of liquid-phase (lp) polarity of single cells and demonstrated its role in metastasis.Material and methodsLp polarity of tumour cells was investigated and characterised in cells from various tumour entities in vitro, in vivo and in liquid biopsies from cancer patients. The role of lp polarity during attachment, adhesion and metastatic seeding of tumour cells was explored in vitro, in vivo, ex vivo and in silico.Results and discussionsWe have identified a novel type of single-cell polarisation termed liquid-phase (lp) polarity. We show that lp polarity is a generic feature of cell lines from different tumour entities and CTCs isolated from cancer patients. We have demonstrated that lp polarity favours attachment and adhesion of tumour cells and thereby contributes to metastatic seeding. The extent of lp polarisation correlated with the metastatic capacity of CTCs in mice and the metastatic potential of cell lines. Importantly, inhibition of lp polarity by different methods reduced metastatic seeding in in vivo models, indicating that lp polarity may constitute a targetable feature of metastasising tumour cells.ConclusionOur research shows that lp polarity is a generic feature of tumour cells in liquid phase constituting a metastatic quality of CTCs that can be targeted to reduce metastatic spreading. Clinical evaluation and further research into molecular regulators of lp polarity may thus enable novel, broad therapeutic strategies against metastatic cancers.
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