Intestinal epithelium fucosylation dysregulation is associated with an age-related tumor microenvironment and higher risk of colon cancer

Aging is a major risk factor in the progression of most malignancies. Colorectal cancer (CRC) is the third highest cause of cancer-related death worldwide, and it affects a disproportionately high number of elderly persons. Despite the early detection of CRC, tumor recurrence continues to be a major concern due to the high prevalence of metastasis among the elderly. In this study, we demonstrate how the mechanisms underlying dysregulation of the local tumor microenvironment increase tumor growth likelihood in the elderly. We found that as a result of aging, gut epithelial cells typically fucosylated their apical surfaces, a process that modifies mucus post-translationally. Notably, the acute fucosylation mechanism protects the gastrointestinal tract against pathogenic infection, and it also aids in homeostatic balance. By studying fucosylation in aging colon cancer epithelial cells, we were able to demonstrate the importance of consistently generating pathogenic fucosylation, which is critical for controlling the steady-state risk of tumorigenesis. In order to identify epithelial subtypes associated with colon cancer-related fucosylation in the elderly, we analyzed a single-cell RNA seq study, which showed a distinct epithelial cell landscape in the aging gut. Based on these data, we hypothesize that chronic inflammation and microbial dysbiosis cause gut epithelial fucosylation in senescent epithelial cells, which in turns increases oncogenic signals and promotes intestinal transformation. Conditions associated by an excess of fucosylation, including elderly colon cancer, may respond therapeutically by removal of involved epithelial cell subtype or reduction of excessive fucosylation in in older adults with colon cancer