Tumor- and immune-derived N-acetyl-β-D-hexosaminidase drive colorectal cancer and stratify patient risk

Non-invasive prognostic markers are needed to improve survival of colorectal cancer (CRC) patients. Towards this goal, we applied integrative systems glycobiology approaches to tumor tissues and PBMCs from CRC patients and matching controls as well as to a CRC patient-derived cell line. Firstly, quantitative glycomics and glycoproteomics revealed that non-canonical paucimannosidic proteins from monocytic and cancer cell origins are prominent signatures in CRC tumor tissues, and that their expression associates with CRC progression. Guided by these associations, we then showed that N-acetyl-{beta}-D-hexosaminidase (Hex) facilitates paucimannosidic protein biosynthesis in CRC cells and is intimately involved in processes underpinning CRC metastasis (adhesion, migration, invasion, proliferation). Finally, Hex activity was found to be elevated in PBMCs and plasma from patients with advanced CRC relative to matching controls while plasma Hex activity correlated strongly with CRC patient survival. Our study opens avenues for better prognostication, disease risk stratification and therapeutic interventions in CRC. HighlightsO_LI* Non-canonical truncated glycans of immune and cancer origins dominate in CRC tumors C_LIO_LI* N-acetyl-{beta}-D-hexosaminidase, a truncating glycoenzyme, drives tumorigenesis in CRC C_LIO_LI* Activity of plasma N-acetyl-{beta}-D-hexosaminidase stratifies risk in CRC patients C_LI