Abstract Paneth cells (PCs), responsible for the secretion of antimicrobial peptides in the small intestine and for niche support to Lgr5 + crypt-base columnar stem cells (CBCs), have been shown to respond to inflammation by dedifferentiating into stem-like cells in order to sustain the regenerative response 1 ,2 . As such, PCs may represent the cells-of-origin of intestinal cancer in the context of inflammation. To test this hypothesis, we targeted Apc , Kras , and Tp53 mutations in Paneth cells by Cre-Lox technology in the mouse and modelled inflammation by dextran sodium sulfate (DSS) administration. PC-specific loss of Apc resulted in multiple small intestinal tumors, whereas Kras or Tp53 mutations did not. Compound Apc and Kras mutations in PCs resulted in a striking increase in tumor multiplicity even in the absence of the inflammatory insult. By combining scRNAseq with lineage tracing to capture the conversion of PCs into bona fide tumor cells, we show that they progress through a “revival stem cell” (RSC) state characterized by high Clusterin ( Clu ) expression and Yap1 signaling, reminiscent of what has previously been observed upon irradiation 3 . Accordingly, comparison of CBC-with PC-derived murine intestinal tumors revealed differences related to Wnt signaling and inflammatory pathways which match the dichotomy of CBCs and injury-induced RSCs 4 between human sporadic colon cancers and those arising in the context of inflammatory bowel diseases. Of note, a striking ∼25% of sporadic colon cancers show expression profiles similar to those of PC-initiated mouse tumors and of patients with an IBD history. The latter can be explained by the low-grade, subclinical inflammation induced by western-style dietary habits, the major colon cancer risk factor, likely to underlie the de-differentiation of secretory lineages of the colon and their acquisition of stem-like and tumor-initiating features. To validate these observations, we applied novel computational methods 5–7 to predict the cell of origin of tumors by matching their genome-wide mutation spectrum with the epigenetic landscapes of colonic cell lineages. While the majority of sporadic colon cancers are predicted to originate from stem cells, in patients with an IBD history, the predominant cell of origin switches to secretory lineages such as goblet cells. Taken together, our results show that, in the context of inflammation, intestinal cancer arises through the dedifferentiation of committed secretory lineages and the activation of the revival stem cell state. The chronic nature of the inflammatory insult caused by western-style dietary habits is likely to underlie similar mechanisms in a significant proportion of sporadic colon cancers and warrants a novel stratification of the cases for improved clinical management.

The origin of intestinal cancer in the context of inflammation