Targeting the non-cancerous cells in cancer tumours

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.

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