The connection between inflammation and tumourigenesis has been well established.However,the detailed molecular mechanism underlying inflammation-associated tumourigenesis remains unknown because this process involves a complex interplay between immune microenvironments and epithelial cells.To obtain a more systematic understanding of inflammation-associated tumourigenesis as welt as to identify novel therapeutic approaches,we constructed a knowledge-based network describing the development of colitis-associated colon cancer(CAC)by integrating the extracellular microenvironment and intracellular signalling pathways.Dynamic simulations of the CAC network revealed a core network module,including P53,MDM2,and AKT,that may govern the malignant transformation of colon epithelial cells in a pro-tumor inflammatory microenvironment.Furthermore,in sliico mutation studies and experimental validations led to a novel finding that concurrently targeting ceramide and PI3K/AKT pathway by chemical probes or marketed drugs achieves synergistic anti-cancer effects.Overall,our network model can guide further mechanistic studies on CAC and provide new insights into the design of combinatorial cancer therapies in a rational manner.