ABSTRACT Distinct from the conventional adenoma–carcinoma pathway, the “serrated pathway” is a molecular pathway postulated for a subset of CRCs that develop from some serrated precursor lesions. In addition, inflammation is a known risk factor for CRC. However, molecular carcinogenic mechanism driving serrated lesion transformation, which is frequently associated with chronic inflammation, remains an important knowledge gap. Previously we found that Notch/HES1 expression is lost in most human sessile serrated adenoma and right-sided CRC and is a ubiquitous marker for IBD-associated serrated lesions and CRC. In addition, Notch/Hes1-loss underlies the gut pathology of an animal model of colitis-associated CRC featuring serrated-like lesions. In this proposal, we will use a combination of approaches (organoid culture, molecular and cellular signaling network analysis of human SSA and serrated CRC, and microbiome deep gene sequencing, etc) and our unique carcinogen-free animal models to study the mechanism by which HES1-loss disrupts epithelial homeostasis, and defining how this process cooperates with a pro-tumorigenic cytokine milieu represented by IL1β to promote carcinogenesis.