Glycosylation: A possible link between diet and stemness in intestinal cancer
Final Report Abstract
According to World Health Organization, cancer is the second leading cause of death worldwide, and was responsible for an estimated 9.6 million deaths in 2018. International Agency for Research on Cancer estimates the new cancer cases to increase to 27.5 million and the cancer-associated deaths to 16.3 million by 2040. Although this is attributed to the growth and aging of the world population in simplistic terms, the common reasons for decreased life expectancy in cancer patients is majorly due to failure in prevention, early diagnosis, or treatment. In this study, we focused on a commonly occurring post-translational modification on proteins, the glycosylation. We elucidated whether changes in glycans could be detected and serve as potential biomarkers in colorectal cancer (CRC) development and progression. Glycans are polysaccharides that play major metabolic roles in cells. Notably, glycosylation can adjust protein function according to the nutritional status of the cell. Given the dramatic increase in the obesity rates worldwide and the CRC incidence in younger adults, we expected that there would be a close correlation between dietary intake, altered glycosylation, and tumorigenesis. Here we showed that high-fat-rich diet induced changes in glycosylation and this was closely associated with tumor development. Pharmacological inhibition of glycosylation decreased tumor progression in a preclinical mouse model and one of the possible mechanisms of this inhibition was achieved via decreased self-renewing capacity of the stem cell compartment in vitro. Furthermore, we confirmed the relevance of these changes and could show altered proteome and glycoproteome in patient-derived tumor organoids providing evidence for differential glycosyltransferase expression in CRC patients. Indeed, when we performed N- and O-glycosylation anaylsis, we identified changes in high- Gal complex bi-antennary, mannosylated, fucosylated and sialylated glycan structures between non-tumor and tumor tissues or organoids. In an attempt to check whether these specific glycan alterations could be imaged via screening technologies, we used bioorthogonal chemistry and could detect GalNAc-positive signals in a magnetic resonance imaging (MRI) scan, a glycan that we found to be increased in tumor tissue from CRC patients. This may be suggestive of that changes in cell surface glycans may serve as a functional readout as a proxy for detecting tumor intrinsic and extrinsic changes in the tumor microenvironment. Altogether this study, starting with addressing the key role of glycosylation changes in a mouse model of diet-induced intestinal cancer and functionally targeting it to the stem cell compartment, then identifying glycosylation-related enzymes and altered glycan structures in CRC patient-derived material, and finally going back to the mouse model and imaging a specific glycan using MRI, implicates diagnostic potentials of glycosylation.
