Pre-cancerous Niche Remodelling Dictates Nascent Tumour Persistence

Interactions between mutant cells and their environment play a key role in determining cancer susceptibility. However, our understanding of how the pre-cancerous microenvironment contributes to early tumorigenesis remains limited. Here, we show that newly emerging tumours at their most incipient stages shape their microenvironment in a critical process that determines their survival. Analysis of nascent squamous tumours in the upper gastrointestinal tract of the mouse reveals that the stress response of early tumour cells instructs the underlying mesenchyme to form a supportive “pre-cancerous niche”, which dictates the long-term outcome of epithelial lesions. Stimulated fibroblasts beneath emerging tumours activate a wound healing response that triggers a dramatic remodelling of the underlying extracellular matrix, resulting in the formation of a fibronectin-rich stromal scaffold that promotes tumour growth. Functional heterotypic 3D culture assays and in vivo grafting experiments, combining carcinogen-free healthy epithelium and tumour derived stroma, demonstrate that the pre-cancerous niche alone is sufficient to confer tumour properties to normal epithelial cells. We propose a model where both mutations and the stromal response to genetic stress together define the likelihood of early tumours to persist and progress towards more advanced disease stages. Overall design: scRNAseq of murine upper gastro-intestinal tract epithelial and stromal cells from early squamous tumours, morphologically normal (internal control) areas, and areas from age-matched (external control) animals.