Researchers have made important inroads into understanding cells
called cancer-associated fibroblasts (CAFs), which are a major
component of tumours.
The team, from Cancer Research UK's London Research Institute
(LRI; now part of the Francis Crick Institute), has
discovered that a protein called YAP plays a critical role in how
CAFs function.
The findings may open up new avenues for therapies aimed at
stopping types of cancer characterised by solid tumours, such as
breast cancer.
Erik Sahai of LRI explained: "Solid tumours are made up of more
than just cancer cells - they are a complex mixture of other cell
types, dissolved proteins and structural and connective tissue.
CAFs are a major component of solid tumours and play an important
role in how tumours grow and how they respond to treatment. Thus,
targeting CAFs might be a logical option for therapies aimed at
halting tumour progression."
To find ways to target CAFs, scientists first need to understand
more about how they operate and the role they play in
tumours.
Dr Sahai and his team worked with colleagues from the Institute
of Cancer Research in London, St George's Hospital in London and
University College London. They isolated CAFs from different stages
of breast cancer and analysed their function and gene
expression.
They discovered that a protein called YAP transcription factor
plays a critical part in the function of CAFs, via the activation
of a number of other proteins. YAP enables CAFs to play roles in
stiffening the structural parts of a tumour. Known as matrix
stiffening, this reinforces the structure of the tumour - and
increased matrix stiffness has been linked to more aggressive
tumours.
The team also found that YAP enables CAFs to drive the
development of new blood vessels throughout a tumour and is linked
to the invasion and spreading of cancer cells to other parts of the
body.
Crucially, the scientists found that matrix stiffening by CAFs
in turn increases the activity of YAP, creating a self-sustaining
positive feedback loop.
Dr Sahai said: "We are always looking for new ways to target
cancers. This study opens up the possibility of targeting
non-cancerous cells within the tumour - in particular, the CAFs. By
disabling their function and reducing changes in the tumour
structure, we hope to make tumours less
aggressive."
The paper, Mechanotransduction
and YAP-dependent matrix remodelling is required for the generation
and maintenance of cancer-associated ?broblasts, is published
in Nature Cell Biology.