Normally cell movement is suppressed by contact with other cells. Scientists have revealed how cancer cells are able to break free of
the physical restraints imposed by their surroundings in order to grow
and spread around the body.
The research could point to new ways to treat or prevent the spread of cancer cells, which is the biggest cause of cancer death.
‘Cancer cells that spread around the body have a broken switch which continually activates a key molecule called YAP.’
Scientists at The Institute of Cancer Research, London, found that
cancer cells that spread around the body have a broken switch which
continually activates a key molecule called YAP.
YAP acts as a 'mechano-sensor', allowing cells to 'feel' the matrix
around them, which they can grasp onto to move around tissues in the
body. YAP can help to overcome the physical restraints by turning on
various genes that are usually switched off.
The new study is published in the journal Cell Systems
and was funded by Cancer Research UK and The Institute of Cancer Research (ICR) itself.
In most cells, YAP's activity is carefully regulated - but the
researchers found that cancer cells that spread are able to produce YAP
all the time, helping them to overcome the physical barriers to
The ICR team systematically switched off 950 different genes in
cancer cell lines grown in the laboratory to work out which ones
influenced YAP signalling. They found that it was partially controlled
by a molecule called beta-PIX.
Beta-PIX boosts YAP activity as the cell binds to the extracellular matrix while moving through tissue.
When the researchers forced the cells to remain stuck to the matrix -
as if the cells had licked an icy pole - YAP activity was even higher.
But, when beta-PIX molecules were depleted, YAP activity was greatly
To find out how YAP activity was controlled in cancer cells, the
team looked at triple-negative breast cancer cells in the lab that were
either derived from a primary tumour or from a site of distant spread.
When the researchers disabled the beta-PIX pathway in cancer cells
from the primary tumor, YAP failed to activate - as would be expected.
But when they did the same to the metastatic cells, YAP did activate.
This suggests invasive cancer cells have broken the pathway that
links beta-PIX to YAP, allowing them to sustain high levels of YAP even
when not bound to the surrounding matrix.
Study leader Dr Chris Bakal, Leader of the Dynamical Cell Systems
Team at the ICR, said: "Our research shows how cancer cells that have
become invasive are able overcome the normal constraints on cell
movement. 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
"Understanding more about the physical processes which constrain and
control the growth and movement of cells can open up exciting new
avenues for cancer treatment, which may have been missed until now."
Dr Emma Smith, science information manager at Cancer Research UK,
said: "When cancer spreads it's a lot more difficult to treat. This
research identifies the signals that can go wrong in cancer cells,
helping them to break free from the tumor. Understanding more about how cancer spreads could be a crucial
first step towards new treatments, but further work is needed to find
out if blocking these signals can stop cancer spreading in people."