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Cell migration regulators may contribute to cancer metastasis

Researchers have shown that tumour protein D52 (TPD52)-like proteins are important for cell migration and cancer cell invasion, revealing a potential therapeutic target against cancer metastasis.

Cell migration

Most animal cells hardly ever stay still. In fact, cell migration is integral for diverse physiological processes, such as immune responses and embryonic development. Disturbances in cell migration and its regulation can thus lead to diseases, such as cancer and inflammation.

Cell-surface receptors, such as integrins, bind and interact with macromolecules of the extracellular matrix (ECM). When cells migrate, receptors are endocytosed to break these interactions and are later recycled back to the cell surface to reinstate contacts with the ECM. This process, known as membrane trafficking (Figure 1), is central in regulating cell migration.

Figure 1: Membrane trafficking in eukaryotic cells. Extracellular molecules (‘cargo’) enter cells through the endocytosis pathway and leave through the exocytosis pathway. Inside the cells, the cargo is transported in vesicles and passes through different cellular compartments. (Credit: Hasegawa et al., 2017)  

Intracellular nanovesicles (INVs) are a novel type of intracellular transport vesicle, participating in recycling and anterograde trafficking pathways. They were recently discovered owing to their association with TPD54, a member of the TPD52-like protein family. These proteins are overexpressed in several cancer types and are associated with aggressive metastases. They have also been implicated in cell migration and adhesion, but their underlying mechanism remains elusive.

TPD52-like proteins bind to INVs

Following their discovery of INVs, researchers at the Centre for Mechanochemical Cell Biology, based in Warwick Medical School, investigated how TPD52-like proteins interact with INVs to affect cell migration and invasion. Their work was recently published in the Journal of Cell Biology.

The researchers identified 2 conserved regions on TPD54 necessary for the protein to associate with INVs. TPD52 and TPD53 were also found to bind to INVs, independently of TPD54. They further identified four INV subsets characterised by their association with at least one TPD52-like protein.

Link to cancer

The researchers then analysed the PanCancer Atlas to identify protein overexpression in a range of cancers. They found that TPD52-like proteins shared similar overexpression profiles with Rab25, a protein that also associates with INVs. Since Rabs are heavily involved in membrane trafficking, this suggests a link between TPD52-like proteins and cell migration and invasion.

To test this hypothesis, the researchers depleted cells of TPD52-like proteins with RNA interference and tracked their migration over different substrates. They observed reduced migration speeds over 2D substrates, fibronectin and laminin. The researchers also tested cellular invasion of 3D structures, a more realistic model for cell movement in the cancer context. TPD52-like protein-depleted cells were unable to invade dense 3D matrices. In contrast, overexpression of TPD52-like proteins enhanced cell motility on both types of substrates.

The researchers further demonstrated that cells depleted of TPD54 had an impaired ability to recycle α5β1 integrins in INVs. Altogether, these results revealed that TPD52-like proteins regulate cell migration by mediating the recycling of integrins during membrane trafficking. 

This study has revealed a mechanistic role of TPD52-like proteins in cell migration, which may explain why their overexpression in cancer cells leads to an aggressive metastatic phenotype. These findings point towards an attractive therapeutic target to slow cancer progression.

Image credit: skylarvision – Pixabay

More on these topics

Cancer / Cell migration / Metastasis