Cell surface carbohydrates and proteins (lectins) that bind them are conspicuously elevated in certain malignancies. These sugar structures and lectins are critically involved in cancer cell motility, invasion and/or migration that ultimately evoke the lethality of cancer. There is a convincing body of evidence suggesting that ss-galactoside-binding lectin, galectin-1 (Gal-1), is a major glycopathogenic mediator of melanoma progression and metastasis. Studies show that melanoma-derived Gal-1 has a major impact on T cell-mediated anti-melanoma immunity. While most have focused on Gal-1 and its functional activity in these malignancy-related events, few have focused on the functional expression of Gal-1 carbohydrate-binding determinants found on the surface of melanoma cells. We have exciting preliminary data showing that human melanoma cells express a robust level of Gal-1-binding carbohydrates, including the membrane protein(s) that display them, that, to our surprise, are conspicuously absent on normal melanocytes and benign melanocytes in mildly dysplastic nevi. Moreover, we have experimental evidence indicating that melanoma cell adhesion molecule (MCAM) is the principal membrane glycoprotein displaying these Gal-1-binding carbohydrates that is also upregulated in malignant melanoma. Differential expression of these Gal-1-binding carbohydrates on distinct glycoproteins, operationally referred to as Gal-1 ligands, could, therefore, functionally correlate with malignant progression of human melanoma. Our central hypothesis is that expression of Gal-1 ligands, namely MCAM, on melanoma cells can not only be used as a biomarker of melanoma progression, but can be functionally associated with malignant transformation. The overall objective of this research project is to analyze the identity, regulation and function of Gal-1 ligands on human malignant melanoma cells and to study the utility of Gal-1 ligands as predictors of human melanoma progression and metastasis. Investigating identity and function of Gal-1 ligands in human melanomas and whether these structures correlate with disease severity and long-term outcome in melanoma patients can be uniquely applied by the tumor biologists and dermato-pathologists collaborating in this proposal. Using new Gal-1 ligand-binding probes developed by our laboratory and our collective expertise in identifying lectin ligands and studying the histopathology of melanomas, the Specific Aims are as follows: (1) To identify and characterize Gal-1 ligands in human melanomas and (2) To study the expression of Gal-1 ligands as predictors of melanoma progression. These studies will implement a unique cohort of human melanoma tissues from the Melanoma Institute of Australia to help determine whether Gal-1 ligand expression correlates with melanoma progression and metastasis. Moreover, we will employ state-of-the-art glycobiological tools to help dissect Gal-1 ligand identity and function. Importantly, our findings will provide novel molecular insights into the glyco-histopathology of melanomas, while offering new glycomic targets for predicting malignancy and/or clinical outcome.

Public Health Relevance

The main goal of this research project is to understand how and why distinct cell surface carbohydrates appear on malignant melanoma cells and not on normal melanocytes. Our data will reveal whether detection of these sugar structures can be used to diagnose malignant melanoma or to predict whether dysplastic melanocytic cells will progress to malignancy. Results from this project will to enhance our overall understanding of the glyco-molecular determinants of human melanoma progression and may provide new methods to help diagnose malignancy and/or predict melanoma aggressiveness.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA173610-02
Application #
8693969
Study Section
Intercellular Interactions (ICI)
Program Officer
Ault, Grace S
Project Start
2013-07-02
Project End
2018-04-30
Budget Start
2014-05-23
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
$349,346
Indirect Cost
$148,071
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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