Cancer Glycomics

Cell surface glycans play a major role in determining cell-cell interactions in the body. Tumor cells are commonly characterized by the expression of glycan epitopes not found on normal cells, or by the overexpression of specific glycans. In fact, some of our earliest work linked changes in glycan composition to tumor progression in esophageal cancer. In collaboration with Dr. Rebecca Fitzegerald’s lab, we identified glycan-based markers discriminating Barrett’s esophagus, an often benign condition, from Barrett’s dysplasia, 59% of patients with which go on to develop esophageal cancer (1).

Current work in our lab seeks to determine the roles glycans play in clinical settings. Beyond their functions as biomarkers, are glycans and their underlying enzymes good therapeutic candidates? We have taken a collaborative, integrative systems-biology approach to answer this question.

Our Areas of Focus

Melanoma

Lectin microarrays, as developed by our lab, require as little as 50 μg of formalin-fixed paraffin-embedded (FFPE) tissue – this enables us to conduct systems-based studies of glycomic changes associated with metastasis in primary melanoma, which typically yield small quantities of sample. In an ongoing collaboration with Dr. Eva Hernando and the Melanoma Research Program in the Perlmutter Cancer Center at NYU Langone Health, we've confirmed miR-30a/d promotes metastasis and IL-10 secretion by suppressing the GalNAc transferase GALNT7 (2), and identified a previously unknown glycan driver of melanoma metastasis, core fucosylation. More specifically, we found that FUT8-mediated core fucosylation drives melanoma metastasis and, when silenced, suppresses invasion and tumor dissemination. It does so by enhancing the cleavage of neural cell adhesion molecule L1CAM, thereby promoting L1CAM's ability to support melanoma invasion (3). Our ongoing collaboration is studying glycans and their corresponding enzymes as potential therapeutic candidates.

Breast Cancer

Recent collaborative work with Dr. Arthur Mercurio's laboratory at the University of Massachuesetts, Worchester, identified an association between breast cancer stem cell (CSC) function and the expression of α2,3 sialylation of O-linked glycans (4). Subsequent work by our collaborators showed that CD44-HA interactions are promoted by core2 α2,3 sialoglycan, resulting in breast CSC function, whereas FUT3, which contributes to sialyl Lewis X (sLeX) production, is preferentially expressed in non-CSCs and antagonizes CSC function (4). This discovery has important implications for tumor diagnosis, prognosis and therapy, yet would not have been possible without our lab's groundbreaking technological contributions to the area of glycomics. We are now focused on identifying new markers for cancer diagnosis with Dr. Karla Williams' lab at the University of British Columbia.

Pancreatic Cancer

In collaboration with Dr. Dafna Bar-Sagi's lab at NYU Langone Medical School, we examined the overlap between the KC mouse model of pancreatic ductal adenocarcinoma (PDA) formation and human PDAC. This analysis revealed both conserved and unique glycan changes in mouse vs. human. We identified α2,6-sialic acid, mediated by the enzyme ST6GAL1, as a promoter of PDAC formation (5). Our lab hopes to build upon this work by identifying the functional significance of aberrant glycosylation in human PDAC with future collaborations.

References

Bird-Lieberman, E.L.; Neves, A.A.; Lao-Sirieix, P.; O’Donovan, M.; Novelli, M.; Lovat, L.B.; Eng, W.S.; Mahal, L.K.; Brindle, K.M.; Fitzgerald, R.C. Molecular imaging using fluorescent lectins permits rapid endoscopic identification of dysplasia in Barrett’s esophagus. Nat. Medicine, 2012, 18, 315-21. doi: 10.1038/nm.2616
Gaziel-Sovran, A; Segura, M.F.; Di Micco, R; Collins, M.K.; Hanniford, D.; Vega-Saenz de Miera, E.; Rakus, J.F.; Dankert, J.F.; Shang, S.; Kerbel, R.S.; Bhardwaju, N.; Yongzhao, S.; Darvishan, F.; Zavadil, J.; Erlebacher, A.; Mahal, L.K.; Osman, I.; Hernando, E. MiR-30b/30d regulation of GalNAc transferases enhances invasion and immunosuppression during metastasis. Cancer Cell, 2011, 20, 104-18. doi: 10.1016/j.ccr.2011.05.027
Agrawal, P; Fontanals-Cirera, B.; Sokolova, E.; Jacob, S.; Vaiana, C.A.; Argibay, D.; Davalos, V.; McDermott, M.; Nayak, S.; Darvishian, F.; Castillo, M.; Ueberheide, B.; Osman, I.; Fenyö, D.; Mahal, L.K. ^‡;; Hernando, E. ^‡A systems biology approach identifies FUT8 as a driver of melanoma metastasis. Cancer Cell, 2017, 31, 804-819. doi: 10.1016/j.ccell.2017.05.007 ^‡Co-corresponding authors
Walker, M.R.; Goel, H.L.; Mukhopadhyay, D.; Chhoy, P.; Karner, E.R.; Clark, J.L.; Liu, H., Li, R.; Zhu, J.L.; Chen, S.; Mahal, L.K., Bensing, B.A.; Mercurio, A.M. O-linked a-2,3 sialylation confers stem cell properties in breast cancer. Science Advances, 2022, 8, eabj9513. doi: 10.1126/sciadv.abj9513
Kurz, E.; Chen, S.; Vucic, E.; Baptiste, G.; Loomis, C.; Agarwal, P.; Hajdu, C.; Bar-Sagi, D. ^‡; Mahal, L.K. ^‡ Integrated systems-analysis of the murine and human pancreatic cancer glycomes reveals a tumor promoting role for ST6GAL1. Molecular and Cellular Proteomics, 2021, 20, 100160. doi: 10.1016/j.mcpro.2021.100160

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F.A.Q.

What is the Canada Excellence Research Chair?

The Canada Excellence Research Chairs (CERC) Program awards universities up to $10 million over seven years to support world‑renowned researchers and their teams to establish ambitious research programs at Canadian universities.

Where is the University of Alberta?

Located in beautiful Edmonton, Alberta, Canada, the Chemistry Department at the UofA is renown for its active research. It is one of the best equipped and well funded departments in Canada.

What is lectin microarray technology?

It is a glycomic technology developed in the Mahal Lab, provide a rapid analysis of the glycome (1-3). These microarrays utilize immobilized carbohydrate-binding proteins at high spatial density to give specific information on the repertoire of glycans present.

Why study microRNA regulation of glycosylation?

miRNA can be used to identify glycosylation enzymes and their corresponding glycans that drive disease states.

How do I apply for grad school?

At the UofA, you do not have to find a supervisor in order to apply. The department has a process in place for students to find a supervisor and join a research group once they arrive to start their program. However, it is recommended for applicants to contact chemistry faculty members whose areas of research are of interest to you. Information about requirements and how to apply can be found here.