Functional Analysis of Galectin-1 Ligands in Melanoma Progression

Summary

Principal Investigator: Charles J Dimitroff
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2013-07-02 - 2018-04-30
more information: NIH RePORT

Top Publications

  1. pmc Human fucosyltransferase 6 enables prostate cancer metastasis to bone
    J Li
    Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
    Br J Cancer 109:3014-22. 2013

Research Grants

  1. Hyaluronan Matrices in Vascular Pathologies
    Vincent C Hascall; Fiscal Year: 2013
  2. SPORE in Soft Tissue Sarcoma
    Samuel Singer; Fiscal Year: 2013
  3. CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE
    UMESH RAMANLAL DESAI; Fiscal Year: 2013
  4. Systems Biology of Glycosylation
    Sriram Neelamegham; Fiscal Year: 2013
  5. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
  6. Molecular Pathogenesis of Basal-like Breast Cancer
    Richard J Baer; Fiscal Year: 2013
  7. WU-MDACC Inter-Institutional Molecular Imaging Center
    David Piwnica-Worms; Fiscal Year: 2013
  8. Four-Dimensional Heterogeneity of Fluid Phase Biopsies in Cancer (4DB-Center)
    Peter Kuhn; Fiscal Year: 2013
  9. SPORE in Lymphoma
    Helen E Heslop; Fiscal Year: 2013
  10. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013

Detail Information

Publications2

  1. pmc Human fucosyltransferase 6 enables prostate cancer metastasis to bone
    J Li
    Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
    Br J Cancer 109:3014-22. 2013
    ..This adhesion is enabled by elevated expression of α-1,3-fucosyltransferases (FTs), enzymes responsible for ESL-mediated bone metastasis in humans. In contrast, the incidence of bone metastasis in mice is rare...

Research Grants30

  1. Hyaluronan Matrices in Vascular Pathologies
    Vincent C Hascall; Fiscal Year: 2013
    ..abstract_text> ..
  2. SPORE in Soft Tissue Sarcoma
    Samuel Singer; Fiscal Year: 2013
    ..abstract_text> ..
  3. CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE
    UMESH RAMANLAL DESAI; Fiscal Year: 2013
    ..End of Abstract) ..
  4. Systems Biology of Glycosylation
    Sriram Neelamegham; Fiscal Year: 2013
    ..v) Validation in animal models of inflammation, peritonitis and COPD (chronic obstructive pulmonary disease), key hypothesis generated using computer simulation and ex vivo experimentation. ..
  5. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  6. Molecular Pathogenesis of Basal-like Breast Cancer
    Richard J Baer; Fiscal Year: 2013
    ..e., metastasis, and develop strategies for therapy. ..
  7. WU-MDACC Inter-Institutional Molecular Imaging Center
    David Piwnica-Worms; Fiscal Year: 2013
    ..Our Molecular Imaging Center also provides a pilot project program for new investigators and a multidisciplinary training program for students, post-docs, and fellows. ..
  8. Four-Dimensional Heterogeneity of Fluid Phase Biopsies in Cancer (4DB-Center)
    Peter Kuhn; Fiscal Year: 2013
    ..The 4DB Center will also serve to disseminate information, education, and training to a new generation of cancer physicists;a generation that will implement the power of physics to conquer the problems of cancer. ..
  9. SPORE in Lymphoma
    Helen E Heslop; Fiscal Year: 2013
    ..The Lymphoma SPORE will also support a Developmental Research Program and a Career Development Program to foster the advancement of pilot translational projects and of young investigators whose research interests focus on lymphoma. ..
  10. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
    ..abstract_text> ..
  11. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  12. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  13. Chicago Prevention and Intervention Epicenter (Chicago PIE)
    ROBERT ALAN WEINSTEIN; Fiscal Year: 2013
    ..The impact on ICU infection and prescribing characteristics of doctors will be assessed. To further assess the interventions, costs of averted outcomes and of the interventions will be compared. OPRIONAL OBEJCTIVE SCORE: 2 ..
  14. Cath B and uPAR si RNA constructs regressed glioma growth
    JOHN P O'BRYAN; Fiscal Year: 2013
    ..This proposal represents a combinational therapeutic approach using a single and bicistronic siRNA construct for cathepsin B and uPAR. This strategy may improve radiotherapy outcomes for the treatment of glioblastomas. ..
  15. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  16. Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia
    Carlo M Croce; Fiscal Year: 2013
    ..abstract_text> ..
  17. SELECTIN MEDIATED CELL ADHESION UNDER HYDRODYNAMIC SHEAR
    Sriram Neelamegham; Fiscal Year: 2013
    ..In the long run, we anticipate that novel strategies to antagonize selectin-ligand binding interactions will be identified from this work that may aid future drug design. ..
  18. Mechanisms of GVHD
    Joseph H Antin; Fiscal Year: 2013
    ..Ultimately we envision an integrated genomic profile that will determine the type of GVHD prophylaxis that will be most effective. ..
  19. Protein-glycan Interactions in the Vascular System
    Lijun Xia; Fiscal Year: 2013
    ..This information may suggest new approaches to treat heart attacks, strokes, and other cardiovascular disorders. ..
  20. Core Center for Musculoskeletal Disorders
    Louis J Soslowsky; Fiscal Year: 2013
    ..abstract_text> ..
  21. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  22. Depression, Biobehavioral Mechanisms, &CHD/Mortality Outcomes
    Karina W Davidson; Fiscal Year: 2013
    ..Doing so will identify potentially more successful and personalized intervention strategies, and accelerate our ability to discover the genes implicated in depression's risk for cardiac disease and death. ..