Phenotypic Plasticity during the Dissemination of Circulating Tumour Cell Clusters: A Model Involving TGFβ1-Mediated Cluster Dissociation, Adherence and Single-Cell Extravasation

Metastasis – the ability of cancer cells to disperse and colonize distant locations in the body, is responsible for the majority of cancer-related deaths. While in the vasculature, tumour cells are referred to as circulating tumour cells (CTCs) and can manifest either as single cells or clusters of cells, with the latter being the most aggressive. Despite their significant role in the metastatic process, the mechanisms through which CTC clusters extravasate and disseminate remain largely unknown. Notably, CTC clusters have been found to contain platelets, which are known to secrete many factors, including Transforming Growth Factor Beta 1 (TGF-β1) – a signaling molecule that has been widely implicated in many aspects of cancer, including the extravasation of single CTCs. To address whether the interaction between platelets and CTC clusters might also facilitate the extravasation of CTC clusters, we evaluated the effect of exogenous TGF-β1 on an experimentally evolved lung cancer cell line that grows as cell clusters that we previously developed and used to investigate the biology of CTC clusters. We found that exogenous TGFβ1 induces the dissociation of clusters and cell adherence. Furthermore, once adhered, cells release their own TGF-β1 and are able to migrate and invade in the absence of exogenous TGFβ1. Based on these findings we propose a model that involves both paracrine and autocrine TGFβ1-mediated phenotypic plasticity resulting in the acquisition of traits that enable the extravasation of CTC clusters as single cells.