Epithelial state-transitions permit inflammation-induced tumorigenesis.

Abstract

Chronic inflammation across tissues is associated with an increased risk of developing cancer1-3. While potentially oncogenic somatic mutations have been demonstrated to persist and expand in healthy organs4-6, what triggers a subset of cells harbouring deleterious mutations to transition into a neoplasm or an aggressive adenoma with poor prognosis7,8 is not well-understood. Unlike normal, healthy cells, benign cells harbouring mutations perceive inflammation in chronic disease differently, potentiating the progression from physiological inflammation to tumorigenesis9. Here, we reveal that a subset of epithelial cells with mutations are poised to transition from pre-neoplastic state to early neoplasm, through rewiring of epithelial IL-1{beta} responses and inflammatory macrophage recruitment. We characterise this process by leveraging a mouse model of biliary tract cancer (cholangiocarcinoma), in which deleterious mutations are introduced to tumour suppressor genes in common cancer pathways (Trp53 and Pten), and by quantifying differences in cell states and corresponding gene expression dependencies in the absence or presence of liver inflammation. Critically, we find that targeting the epithelial-derived signals of tissue-wide inflammation (namely COX2) is insufficient to limit tumorigenesis; rather, targeting the reactivation of oncogene-induced developmental signals, such as NOTCH, prevents this pre-neoplastic to neoplastic transition, demonstrating that oncofoetal switching is a pharmacologically-tractable target in patients with a high risk of developing cancers on the background of inflammation.