Investigations into the mechanisms involved in the dissemination of circulating tumour cell clusters
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Date
2022-12
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University of New Brunswick
Abstract
Metastasis – the ability of cancer cells to disperse and colonize distant locations in the body, is responsible for most 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 involved in the extravasation and dissemination of CTC clusters remain largely unknown. Notably, CTC clusters have been found to contain platelets, which can secrete many factors, including the Transforming Growth Factor Beta 1 (TGF-β1) – a signalling molecule implicated in many aspects of cancer, including the extravasation of single CTCs. To address whether the interaction between platelets and CTC clusters might facilitate the extravasation of CTC clusters, here I evaluate the effect of exogenous TGF-β1 on an experimentally evolved lung cancer cell line that grows as cell clusters. I show that exogenous TGF-β1 induces the dissociation and adherence of clusters. Furthermore, once adhered, cells release their own TGF-β1 and are able to migrate and invade in the absence of exogenous TGF-β1. Based on these findings, I propose a model involving TGF-β1-mediated phenotypic plasticity that enables the extravasation and dissemination of CTC clusters as single cells. To evaluate the specific pathways activated during these processes, I used transcriptomic analyses to investigate TGF-β1-induced changes in gene expression. I found that the ability to adhere in response to TGF-β1 involves the upregulation of genes associated with the TGF-β1/Smad2/3, Wnt/β-catenin and EGFR signalling pathways. The upregulation of EGFR allows for the possibility that currently available drugs targeting EGF-signalling might also be effective against CTC clusters. Overall, this study highlights the need to better understand the molecular mechanisms involved in the dissemination of CTC clusters as a means to develop new therapeutic strategies to specifically affect this important step in the metastatic cascade and improve clinical outcomes.