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

Sep 23, 2026

Aberrant glycosylation drives colorectal cancer onset, progression, and metastasis, with evidence for frequent up-regulation of glycans bearing α2,3-/α2,6-sialic acid and fucose. This study applies lectin-directed protein aggregation therapy (LPAT) to hypersialylated and hyperfucosylated colorectal cancer cells using cancer-activated lectin multivalency. After screening against five CRC cell lines, the most effective targeting was seen in hyperfucosylated/matrix metalloproteinase-9-overexpressing HCT-116 cells, reducing invasion and migration. In a metastatic mouse model, hyperfucosylation targeting prevented liver and kidney tumor development, supporting LPAT as a strategy to discriminate highly metastatic CRC glycosylation for prevention.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

Rationale for glycan-targeting therapies

Glycosylation changes in cancer: hypersialylation and hyperfucosylation

Relevance to colorectal cancer and metastasis

Results and discussion

LPAT targeting strategy and screening across CRC cell lines

Functional effects on invasion and migration

In vivo testing in a metastatic colorectal mouse model

RESEARCH ARTICLE Lectin-Directed Protein Aggregation Therapy toward Hyperfucosylated and Hypersialylated Metastatic Colorectal Cancers Xiao Han1, Yufei Li1, Yiling Liu1, Shenghai Shen2, Yitong Shen2, Li-Sheng Zhang1,2*, and Kenward Vong1* 1Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong, China. 2Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China. *Address correspondence to: [zhangls@ust.hk](zhangls@ust.hk) (L. -S.Z.); [kvong@ust.hk](kvong@ust.hk) (K.V.) 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 tumorassociated 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. Citation: Han X, Li Y, Liu Y, ShenS, ShenY, Zhang L-S, Vong K. LectinDirected Protein Aggregation Therapy toward Hyperfucosylated and Hypersialylated Metastatic Colorectal Cancers. Biomater. Res. 2026;30:Article 0394. [https://doi](https://doi). org/10.34133/bmr.0394 Submitted 2 February 2026 Revised 20 June 2026 Accepted 27 June 2026 Published 17 July 2026 Copyright © 2026 Xiao Han et al. Exclusive licensee Korean Society for Biomaterials, Republic of Korea. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License (CC BY 4 .0) . Introduction As cancer is one of the leading causes of death worldwide, there has been considerable interest in developing targeting therapies that can selectively act to eradicate cancerous cells while sparing normal, healthy tissues [1] . This principle is the basis behind the engineering of monoclonal antibodies, which are therapeutics that act to target cancers through the recognition of specific cancer biomarkers [2]. Despite their success, antibody therapies have continually struggled with regard to targeting glycanrelated cancer biomarkers. Since the late 1960s, glycans present on the surface of cancer cells have been found tobe markedly altered compared to those of normal cells. Deeper investigations revealed that tumor-associated glycans are characterized by changes in glycan composition, truncation, or modification of branching points [3]. These alterations were subsequently found to be linked to carcinogenesis, immune evasion, and even metastasis [4]. Two of the most well-known cancer-associated glycosylation changes found in cancers are hypersialylation and hyperfucosylation [5]. Sialic acid is a 9-carbon sugar mainly found asa terminal monosaccharide linked to other glycans through either α2,3-or α2,6-linkages. In cancers, hypersialylation has been linked to the up-regulation of sialyltransferases, which are enzymes that catalyze the transfer of sialic acid onto carbohydrate chains. For example, evidence has shown that ST3Gal variants (α2,3-sialyltrans

FAQs

What is lectin-directed protein aggregation therapy (LPAT) and how does it target cancer cells?

LPAT uses cancer-activated lectin multivalency, where tumor-associated proteases trigger self-assembly of multivalent lectin complexes. This enables selective impairment of metastatic activities of cancer cells.

Which colorectal cancer cell line showed the strongest LPAT targeting in the study?

The study identified the hyperfucosylated/matrix metalloproteinase-9-overexpressing HCT-116 cell line as the most effective target. Treatment produced significant reductions in invasion and migration.

How did hyperfucosylation targeting perform in an animal metastatic colorectal cancer model?

In a metastatic colorectal mouse model, hyperfucosylation targeting prevented liver and kidney tumor development, indicating a viable preventive approach.

Sep 23, 2026

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