Cancer cells’ ability to break free and spread arises from ‘broken switch’

A new study reveals fresh insights into how cancer cells escape from primary tumors and spread to other parts of the body. Researchers have discovered that such cells have a “broken switch” that enables them to shrug off their physical constraints.

The researchers found that cancer cells that have traveled to other parts of the body have a switch that is ‘jammed on,’ allowing them to escape the physical controls that would normally stop them from growing and spreading.

A report on the discovery – by the Institute of Cancer Research (ICR) in London, United Kingdom – is published in the journal Cell Systems.

Study leader Dr. Chris Bakal, who heads the dynamical cell systems team in ICR’s Division of Cancer Biology, says that their investigation shows how invasive cancer cells have acquired the ability to overcome the normal constraints on cell movement.

The vast majority of cancer deaths occur because the cancer spreads from the primary tumor to other parts of the body.

This process of cancer spread is called metastasis, and it arises because cancer cells acquire the ability to migrate. Finding ways to prevent or halt metastasis could save many lives.

Researchers have already discovered many physical and chemical differences between metastatic and non-metastatic cells.

In 2013, for example, a large group of scientists published a catalog describing the mechanical properties of metastatic cells, how they stick to surfaces, migrate, respond to oxygen, and produce protein.

However, what has not been so clear is what happens at the molecular level to disrupt signaling that changes the character of the cell and its relationship to its environment.

‘Broken switch’ allows continual YAP production

In the new study, the ICR team describes how it found that cancer cells that spread around the body have a broken switch that continually activates an important molecule called YAP.

YAP acts as a “mechano-sensor” that allows the cell to “feel” its surroundings – such as how it adheres to the extracellular matrix. The extracellular matrix is a non-cellular component comprising water, proteins, and other molecules secreted by cells that hold them place and regulate key biochemical and biomechanical signals.

Normally, a cell’s ability to grasp onto and move around tissues in the body is tightly constrained by its relationship to the extracellular matrix and other cells. However, YAP can overcome these physical constraints by switching on genes that are usually turned off.

The team found that unlike normal cells – where YAP production and activity are carefully regulated – cancer cells that are able to spread produce YAP all the time, allowing them to escape their physical constraints.

The researchers found that a molecule called beta-PIX partially controls YAP signaling. They discovered it by systematically switching off 950 genes one by one in laboratory-grown cancer cells.

Broken link between beta-PIX and YAP

In further experiments, the team discovered that beta-PIX boosts YAP activity as the cell adheres to the extracellular matrix while moving through tissue.

When cells were forced to remain stuck to the matrix, YAP activity was even higher. However, it greatly reduced when levels of beta-PIX molecules depleted.

The researchers then looked more closely at how the link between beta-PIX and YAP behaves in metastasis. They examined it in triple-negative breast cancer cells from primary tumors and in cells from secondary tumors.

As expected, tests showed that disabling the beta-PIX pathway in cancer cells from primary tumors failed to activate YAP. However, doing the same to metastatic cells in secondary tumors did activate YAP.

The researchers suggest this shows that the link between beta-PIX and YAP is broken in metastatic cells, thereby allowing them to maintain high levels of YAP even when not bound to the extracellular matrix.

“Cancer cells that have spread around the body have a switch which is jammed on – allowing them to produce a molecule called YAP all the time. This allows them to keep growing and spreading throughout the body, ignoring the physical controls that would normally stop this happening.”

Dr. Chris Bakal