Jones Group

Pre-cancer

Our group studies how normal cell behaviour is altered by mutation in aging and the earliest stages of cancer development. We focus on normal skin epidermis and the lining of the oesophagus which acquire a high burden of mutations by middle age. Our approach combines deep sequencing of normal human tissues with novel 3D culture methods, gene editing, live imaging, single cell analysis and quantitative modelling. We have disccovered that normal tissues are extensively colonised by mutant cells. Some mutations increase cancer risk while others may decrease it. We are now researching how to redirect evolutionary selection to reduce the burden of the most deleterious mutations.

We focus on three key areas:

• Mutations in normal tissues
• The competitive fitness of mutant cells
• The earliest stages of tumour development
  

To find out more about each project, read below

Cancer arises after extensive exposure to agents that mutate DNA. Examples include ultraviolet light in sunshine on skin cells, and aging and alcohol use in the oesophagus. However, these tissues can continue to look and function normally despite accumulating a large proportion of cells that are carrying mutations that are common in cancers and may impact tissue aging. Understanding the processes that restrain mutant cells and how we can redirect the Darwinian like evolutionary processes that shape the patchwork of mutant cells in our aging

Cancer arises after normal cells accumulate changes in their DNA. These may arise from ageing or from exposure to factors in the environment such as sunlight in skin cells, or alcohol in the oesophagus. Normal tissues accumulate a large proportion of cells with mutations commonly found in cancers. We aim firstly to understand the Darwinian like evolutionary processes that shape the patchwork of mutant cells in our aging tissues and secondly the earliest stages of how tumours emerge from normal tissues.   We then apply these insights to identify interventions that can deplete the mutations that drive cancer development from normal tissues, with the aim of stopping cancer before it starts.

Mutations in normal tissues

We devised an approach to map cells carrying mutations in normal skin and oesophagus, finding a high burden of cells with mutations found in cancer. We are now exploring how mutations and other genome abnormalities vary with age, lifestyle factors such as sun exposure, smoking or alcohol, changes in the immune system, and exposure to drugs or radiation.

The competitive fitness of mutant cells

We have identified mutations that give cells a competitive advantage over their neighbours, allowing them to colonize normal tissues. By using large scale gene editing in 3D cultures of tissues we can find how these mutations make cells ‘fitter’ and uncover potential weaknesses that can be targeted to remove the mutant cells from tissues without damaging normal cells.

The earliest stages of tumour development

We can visualize microscopic tumours as they emerge from normal oesophageal tissue and study the mutations they carry.  Many, but not all, of these micro-tumours are lost.  The survivors may go on to develop into cancers.  Understanding the processes involved will guide developing interventions to eliminate more micro-tumours before they make it into cancer.