Paired mutation calling and spatial transcriptomics identify cellular neighborhoods associated with the neoplastic...

In the progression from inflammatory bowel disease to associated cancer, the clonal mutational landscape shifts from selection of mutations in inflammatory genes to selection for cancer-driver mutations. How prevalence and expansion of either type of mutant clones could be impacted by the cellular environments in which they arise and how this affects the neoplastic outcome of colitis remains unknown. Here we combine in vivo lineage tracing, in silico modeling, mutational profiling and spatial transcriptomics in a mouse model of colitis-associated tumorigenesis to capture clone fates associated with chronic inflammation. We identify epithelial- and immune-enriched neighborhoods and propose a model in which establishment of a reparative tissue environment facilitates tumor initiation by promoting the selection and expansion of pro-oncogenic clones, reducing the span of inflammation-resistant neighborhoods containing nononcogenic clones.