Scientists have discovered two genes that help melanoma cells change their shape as they move through different tissues. The finding reveals one of the tricks cancer uses to spread through the body — and could eventually provide new targets for drugs designed to stop metastasis.

One of cancer’s most dangerous characteristics is its ability to move.

A tumour that remains confined to its original location can often be treated far more effectively than cancer that has spread to other parts of the body.

But travelling through the human body presents cancer cells with a physical problem.

Different tissues create completely different environments.

To survive the journey, cancer cells have developed a remarkable ability: they can change their shape.

From a drill to a ball

Researchers from The Institute of Cancer Research, London, and Imperial College London investigated how melanoma skin-cancer cells adapt their shape to their surroundings.

In dense tissue, such as bone, cancer cells can become elongated — almost drill-shaped — helping them push through the surrounding material.

In softer environments, they can become rounder and more flexible, enabling them to squeeze through tissue and enter the bloodstream.

The mystery was how a cancer cell recognises its physical environment and selects the appropriate shape.

The new research has identified part of the mechanism.

Watching 60,000 cells in three dimensions

A major obstacle in cancer research is that cells have traditionally been studied on flat, rigid laboratory surfaces.

But a human body is not two-dimensional.

The researchers therefore developed a system that allowed them to investigate melanoma cells in environments that more closely resemble real human tissue.

They used stage-scanning oblique plane microscopy (ssOPM), an advanced imaging technique capable of producing three-dimensional images of large numbers of cells.

Some cells were placed on flat, rigid surfaces. Others were embedded inside a soft 3D collagen hydrogel.

The researchers ultimately analysed images of approximately 60,000 cells.

Switching genes off

The team then systematically switched off different genes and observed what happened to the cells.

This allowed them to connect genetic activity with physical shape.

Two genes stood out:

TIAM2 and FARP1.

When these genes were disrupted, melanoma cells became less capable of changing shape appropriately in response to their environment.

That suggests the genes are part of the machinery that allows cancer cells to sense their surroundings and adapt their physical form.

Why metastasis is so dangerous

This matters because most cancer deaths are associated with cancer spreading from its original tumour to other parts of the body.

Professor Chris Bakal, Professor of Cancer Morphodynamics at The Institute of Cancer Research, explained that once cancer becomes metastatic, it can become much more difficult to treat.

Understanding how cancer cells travel is therefore a major research priority.

The discovery of TIAM2 and FARP1 provides two potential points at which scientists might eventually interfere with that process.

Could the shape-shifting mechanism be blocked?

The researchers believe the two genes could potentially become drug targets.

That does not mean that a treatment targeting them already exists.

The work is fundamental and preclinical research.

But both genes produce proteins with structural similarities to proteins already being investigated by pharmaceutical researchers. That makes them potentially interesting candidates for future drug development.

If scientists could prevent melanoma cells from adopting the shapes they require to move through different tissues, it might become possible to make metastasis more difficult.

In other words, instead of attacking the cancer cell only by trying to kill it, a future therapy might also try to stop it travelling.

A new way of studying cancer

The imaging technology may prove just as important as the two genes.

Professor Chris Dunsby of Imperial College London’s Department of Physics said this was the first study to apply high-content oblique plane microscopy to many thousands of cells in three dimensions.

The technique could now be used to investigate many other questions in cancer biology.

The researchers are also developing AI-based technologies that analyse these three-dimensional cell images and attempt to predict which drugs may be effective.

Such approaches could eventually accelerate the early stages of drug discovery.

Cancer is also a physical disease

The study highlights a broader change in the way scientists understand cancer.

Cancer is fundamentally a disease involving genetic and molecular abnormalities.

But those abnormalities ultimately affect a physical cell.

And that cell must interact with its environment.

It has to push.

Squeeze.

Attach.

Detach.

Change shape.

And sometimes travel through the bloodstream before establishing a new tumour elsewhere.

Understanding those physical properties adds another dimension to cancer biology.

The melanoma cells observed in this research are not passive objects.

They continually adapt themselves to the world around them.

Scientists are now beginning to understand the genetic machinery that makes that adaptation possible.

And if that machinery can eventually be disrupted, one of cancer’s most dangerous abilities — its capacity to spread — may become a little more vulnerable.

Source: Based on “Shape-shifting cancer cell discovery reveals potential skin cancer drug targets,” published by Imperial College London on 17 April 2024. The research was conducted by scientists at The Institute of Cancer Research, London, and Imperial College London and was funded by organisations including Cancer Research UK and the Engineering and Physical Sciences Research Council. The underlying study, “Environmentally dependent and independent control of 3D cell shape,” by Lucas G. Dent and colleagues was published in Cell Reports.