Colitis is a chronic inflammatory disease and an established risk factor for developing colorectal cancer, yet the role of inflammation in tumour initiation was previously unclear. Nagaraja et al. now show in mice that colonic stem cells form an epigenetic memory of inflammatory exposure that is inherited and cooperates with oncogenic mutations to drive colorectal cancer.

Organoids derived from tissue taken at the chronic injury phase displayed a regenerative, hyperplastic morphology and increased proliferation that persisted for over 34 days in culture, indicating that inflammatory memory persists after removal from the tissue microenvironment and is stem cell intrinsic. To test whether this memory is heritable and epigenetically mediated, the authors developed SHARE-TRACE, a method integrating SHARE-seq with clonal tracing. Using this approach, AP-1 emerged as the only transcription factor family retaining inflammatory memory both in vivo and ex vivo. Further experiments revealed that acute inhibition of AP-1 DNA binding reduced proliferation in colitis-derived organoids but not in controls, whereas organoids resumed the colitis-associated phenotype following prolonged inhibition. These results suggest that AP-1 facilitates but is not required for permanent maintenance of memory phenotypes.