The role of polarisation of circulating tumour cells in cancer metastasis

Abstract

Metastasis is the spread of cancer cells from a primary tumour to a distant site of the body. Metastasising tumour cells have to survive and readjust to different environments, such as heterogeneous solid tissues and liquid phase in lymph- or blood circulation, which they achieve through a high degree of plasticity that renders them adaptable to varying conditions. One defining characteristic of the metastatic process is the transition of tumour cells between different polarised phenotypes, ranging from differentiated epithelial polarity to migratory front-rear polarity. Here, we review the polarisation types adopted by tumour cells during the metastatic process and describe the recently discovered single-cell polarity in liquid phase observed in circulating tumour cells. We propose that single-cell polarity constitutes a mode of polarisation of the cell cortex that is uncoupled from the intracellular polarisation machinery, which distinguishes single-cell polarity from other types of polarity identified so far. We discuss how single-cell polarity can contribute to tumour metastasis and the therapeutic potential of this new discovery.

Keywords: Actin; Adhesion; Attachment; CTC; Cancer; Single-cell polarity.

Fig. 1

Polarisation states of tumour cells. The illustrations depict the localisation of some of the main polarity regulating modules in an epithelial cell displaying apical–basal polarity and planar cell polarity (PCP) (a), a migrating cell displaying front–rear polarity (b) or a cell in liquid phase displaying single-cell polarity (c). The inset in c shows a tomogram of the pole of an SkMel2 cell in suspension, adapted from [20], showing plasma membrane (cyan), ER and nuclear envelope (magenta), mitochondria (green) and lipid droplets (yellow). Scale bar 1 μm. While the molecules sustaining the different polarised phenotypes are the same in the different types of polarity, their localisation and interconnections differ. For details see main text. TJ tight junction, AJ adherens junction, PI3K phosphoinositide-3-kinase, PIP2 phosphatidylinositol 4,5 bisphosphate, PIP3 phosphatidylinositol 3,4,5 trisphosphate

Fig. 2

Exit of CTCs from the circulation. a Attachemnt, adhesion and extravasation of CTCs in larger vessels. CTCs can attach to the endothelial wall of blood vessels. During active adhesion to the vessel wall, cortical single-cell polarity is coupled to intracellular polarity modules, leading to nucleo-centrosomal alignment necessary for migration and extravasation. b Mechanical trapping and extravasation of CTCs in smaller vessels. CTCs get passively arrested in blood vessels of small diameter. Similar to a, extravasation and migration require coupling of cortical and intracellular polarity modules and nucleo-centrosomal alignment

Fig. 3

Types of polarity during tumour progression. Overview of the process of carcinogenesis and metastasis (adapted from [20]). Insets show the steps at which specific types of polarity are involved. Healthy cells (grey) can accumulate mutations leading to uncontrolled growth, evasion of cell death and development of a tumour (yellow). Tumour cells can undergo EMT (yellow to blue), leading to further dedifferentiation and shift to a migratory phenotype (blue) favouring invasion, migration and intravasation into the lymph or blood circulation. Circulating tumour cells can exit the circulation by mechanisms shown in detail in Fig. 2. For further details see Figs. 1, 2 and main text