An international team of scientists has discovered how cancer cells exposed to high-viscosity environments change the way they move to improve their invasiveness and favour metastases. The studies provide new targets for the design of possible cancer therapies.

Understanding how cancer cells move and make decisions in these confined environments is important as 90% of cancer-related deaths involve metastases.

The labs of Dr. Konstantinos Konstantopoulos of Johns Hopkins University and of Dr. Miguel A. Valverde of UPF, together with teams from the USA and Canada, have been working together over the past six years to unravel how cancer cells use ion movement through mechanically activated ion channels -stimuli that deform cell membranes- to adapt their movement to different mechanical stresses and environments.

The results of this research have been published in two studies in the journals Nature and Nature Communications.

In these two new studies, the scientists asked themselves:
1) how cancer cells polarise ion transport mechanisms in the leading edge and trailing edge of the cells to move through narrow spaces; and
2) how cancer cells optimise movement when fluid viscosity is high.

To address these important questions, they studied the movement of cells in three-dimensional media generated using bioengineering techniques, which resemble the pathways along which cells normally move in our bodies.

Key proteins were located within the cell using high-resolution microscopy, cell volume, ion movements, and electrical activity were recorded, and they evaluated how the expression of different genes that are important to the progression of cancer changes.

In the first study, published in Nature Communications, the international team found that cancer cells can move in confined spaces by simply taking in water at the leading edge of the cell and releasing it at the trailing edge.

They do so without the need to establish molecular interactions with the walls of the surrounding tissue. "It works like a hydraulic propeller, similar to the device that Tom Clancy fictionalised to propel a submarine in his novel The Hunt for Red October," Dr. Miguel Valverde explains.

"Cancer cells can move in confined spaces by simply transferring water from the leading edge to the trailing edge of the cell."

In real life, this is possible because, in their leading edge, the cells accumulate an ion transport system, the sodium/proton exchanger (NHE1), which charges the cell with sodium which increases osmotic pressure and favours the entry of water into the cell.

At the same time, cancer cells concentrate the SWELL1 protein in their trailing edge. SWELL1 (also known as LRRC8A) is a chloride channel activated by increases in cellular water content that facilitates the exit of chloride and water.

The end result of the coordinated action of these two ion transport systems on the leading and trailing edges enables cell movement. More importantly, the study shows that the activity of these two systems is essential for the movement of cancer cells outside of blood vessels and in the development of metastasis.