Lectin-Directed Protein Aggregation Therapy toward Hyperfucosylated and Hypersialylated Metastatic Colorectal Cancers

Aberrant glycosylation is a well-known pathological alteration that accompanies tumor onset, progression, and eventual metastasis. For colorectal cancers, there is strong evidence to show that glycans containing α2,3-sialic acid, α2,6-sialic acid, and fucose are frequently up-regulated. In this work, we report the application of lectin-directed protein aggregation therapy (LPAT) to target hypersialylated and hyperfucosylated colorectal cancer cells. This system relies on the concept of cancer-activated lectin multivalency, where tumor-associated proteases can elicit the self-assembly of multivalent lectin complexes that can selectively impair the metastatic activities of cancer cells. After screening LPAT agents against a panel of 5 colorectal cancer cell lines, the most effective targeting was identified against the hyperfucosylated/matrix metalloproteinase-9-overexpressing HCT-116 cell line, which showed significant reductions in invasion and migration upon treatment. Experiments then showed that hyperfucosylation targeting could be used as a viable approach to prevent liver and kidney tumor development in a metastatic colorectal mouse model. Overall, this work highlights the viability of using LPAT to discriminate the aberrant glycosylation of highly metastatic colorectal cancer cells as a means to prevent their onset and progression.