Using synthetic biology and quantitative analysis to understand differences in tolerance to tumorogeneic mutations

Background:

Healthy tissues often harbour tumorogeneic mutations. It is not entirely clear why such mutations are sometimes tolerated but at other times lead to disease.  There is an increasing appreciation of that surrounding healthy cells (the tumourogenic ‘niche’) play a critical role, but it is not clear how these cells sense and response to mutant cells.  If we are able to uncover the molecular and cellular basis of this ‘sense and response’ mechanisms, we can then determine how genetic differences between individuals could explain different “niche responses” and therefore different susceptibilities to disease and to therapy. 

In this project we combine two novel synthetic biology technologies to address this question. The Lowell lab have developed a novel ‘neighbour labelling’ system that will enable multi-omic analysis and quantitative image analysis in order to characterise the behavoir of cells within the niche surrounding early cancer cells.  Our close collaborators in the neighbouring Pollard Lab have expertise in developing highly specific synthetic enhancers that can be used to deliver ‘neighbour labelling” machinery to particular cell states, including pre-neoplastic or more advanced tumorogeneic states. 

This approach will generate quantative data including spatial and temporal information about how cells respond to mutations in their neighbours, based on live imaging and on scRNAseq analysis of synthetically-labelled neighbours of mutant cells. The Schumacher lab have expertise in mathematical modelling of cell-cell interactions, including spatial analysis of the cancer niche.