Sialic Acid Metabolic Engineering of Breast Cancer Cells Interferes with Adhesion and Migration

Abstract

Breast cancer is the most frequent cancer diagnosed in women and the second most common cancer-causing death worldwide. The major problem around the management of breast cancer is its high heterogeneity and the development of therapeutic resistance. Therefore, understanding the fundamental breast cancer biology is crucial for better diagnosis and therapy. Protein sialylation is a key posttranslational modification of glycoproteins, which is also involved in tumor progression and metastasis. Increased expression of sialic acids (Sia) can interfere in receptor–ligand interactions and might protect tumor cells from the immune system. Furthermore, Sia content on the cell membrane plays a role in cancer resistance towards chemo- and radiation therapy. In this study, we glycoengineered MCF-7 breast cancer cells using a series of non-natural Sia precursors, which are prolonged in their acyl side chain. We observed a significant reduction in the natural Sia (N-Acetylneuraminic acid) expression after cultivation of MCF-7 cells with these Sia precursors. In addition, the expression of polySia, a unique glycosylation of the neural cell adhesion molecule NCAM, which interferes with cell adhesion, was decreased. We conclude that sialic acid engineering i) opens up novel opportunities to study the biological role of Sia in breast cancer and ii) provides a toolbox to examine the sialic acid-dependent complex cellular alterations in breast cancer cell biology.

Sialic acids in gynecological cancer development and progression: Impact on diagnosis and treatment

“…These findings are consistent with a growing body of literature demonstrate the hypersialylation and increased expression of sialylated antigens in prostate, breast, bladder, and testicular cancer and malignancies in the bone marrow 79‐86 . Generally, there were many similarities between gynecological cancers and other cancers, whereas the type of sialyltransferases that are overexpressed varied per cancer type.…”

Re-Expression of Poly/Oligo-Sialylated Adhesion Molecules on the Surface of Tumor Cells Disrupts Their Interaction with Immune-Effector Cells and Contributes to Pathophysiological Immune Escape

“…Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases scattering and motility of MCF7 breast cancer cells [474,475]. The cytoplasmic domain of L1-CAM interacts intracellularly with ankyrin and kinases [476].…”

The Applications of Metabolic Glycoengineering

“…Metabolic glycoengineering (MGE) - a technique where monosaccharide analogs are introduced into the metabolic pathways of a cell and are biosynthetically incorporated into the glycocalyx on cell membrane - has been shown to be precious for engineering cellular surface properties to allow manipulation of cellular behaviour and function using natural or unnatural functional groups ( Du et al, 2009 ; Nagasundaram et al, 2020 ). Over the last 2 decades, more than 20 unnatural mannosamines that are suitable for MGE, have been introduced.…”

“…Findings from other research have revealed significant improvement in adhesion ability of leukocytes, Jurkat cells, neural cells, mesenchymal stem cells (MSCs) and A549 cells after treatment with ManNAc analogs ( Du et al, 2009 ; Du et al, 2011 ; Koo et al, 2015 ; Koo et al, 2016 ; Lo et al, 2016 ). However, Nagasundaram et al( Nagasundaram et al, 2020 ) found a marked reduction in adhesion of MCF7 breast cancer cells to laminin upon treatment with different ManNAc analogs. In addition, they found that application of all non-natural sialic acid precursors downregulated N-acetylneuraminic acid (Neu5Ac) and polysialic acids (polySia), and further suppressed adhesion and migration.…”