April 1 2020

A novel mechanical signalling pathway that could influence the development of cancers has been discovered in cultured melanoma cells by scientists in Sydney and Germany.

Researchers from the ARC Centre of Excellence in Advanced Molecular Imaging (Imaging CoE) at the UNSW Node, have identified a molecule that allows melanoma cells to sense their physical environment and guide interactions with their surrounding cells and tissues in a way that could regulate the early steps of a metastatic cascade.

In an advanced online publication in the journal eLife , the team led by Dr Kate Poole presents evidence of a novel mechanical signalling pathway in melanoma cells that regulates cell binding. In this process, they identify a central role for Elkin1– a molecule with previously unknown function expressed in melanoma cells, but not precursor melanocytes. Elkin1 is required for the cells to convert mechanical inputs into localised electrical signals, a process known to depend on mechanically activated ion channels.

“When we experimentally deleted Elkin1, melanoma cell migration slowed down, and it led to the breakup of tumour masses,” says Dr Poole, Associate Investigator to the Imaging CoE and group leader at UNSW Medicine’s Single Molecule Science.

“Using atomic force microscopy, we could see that melanoma cells without Elkin1 have a lower attachment or adhesion force to each other, and there’s a breakdown in cell-to-cell contact so that they form looser tumour masses,” says PhD student Amrutha Patkunarajah, one of the first authors of the study.

The results from this study using cells lines point to promising areas for further research to better understand the development of cancers in animals and humans.

“This is a really interesting finding that opens up a whole raft of new avenues of investigation. And we’re keen to look further into how these types of mechanical signalling pathways might influence the development of cancers,” says Dr Poole.

Mechanosensitive ion channels
As cells move through the body, they encounter different mechanical forces – exerted by other cells and their surroundings – that are converted to electrical or biochemical signals via mechanosensitive ion channels. This specific class of proteins respond to minute scale physical input to influence the behaviour of cells. But these channels are not well understood.

“Only a handful of mechanosensitive ion channels have been identified in mammals so far, with the best characterised one being PIEZO1, which was only discovered 10 years ago,” Dr Poole says.

“The fact that we now have another molecule to work with, that is independent of PIEZO1, and that is associated with very sensitive mechanically activated currents is very exciting.”

To investigate the interactions between cells and their microenvironment, the research team use a culture system previously developed by Dr Poole with colleagues at Max Delbrück Center for Molecular Medicine in Germany – where cells are grown on top of tiny elastic pillars.

“When a minute force is applied locally at the cell-substrate interface we can measure electric currents in the cell. These super fine forces mimic those encountered by the cells as they move through the body. Other methods available can be too aggressive,” says Ms Patkunarajah.

“If we had taken a traditional methodology for studying cell response to mechanical forces, like stretching the membrane, you would not see this activity because Elkin1 does not respond to membrane stretch,” says Dr Poole.

The micropillar culture system has been instrumental in making discoveries recently published by Dr Poole and her team on how different cells sense mechanical forces, including in neuropathic pain, tuning of senses, and mechanical signalling in primary chondrocytes.

This article was first published by SMS

Feature image: Melanomas form tight tumour masses when they express Elkin (pink), and loose tumour masses when Elkin1 is deleted (cyan)