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 IL1? to promote carcinogenesis.
Chronic inflammation is a risk factor for colorectal cancer (CRC). A subset of CRC develops through the ?serrated pathway? which often shows characteristic immune microenvironment. In this study, we will use novel colitis-associated CRC models and human specimen cohorts to study how epithelial Notch/Hes1-loss orchestrates a pro- tumorigenic immune microenvironment. The biomarkers identified from studying the pre-malignant forms and inflammation-associated CRC in the serrated pathway will have significant interventional impact.
