Analysis of galectin-8 and its ligands in melanoma progression

With successes in cancer treatment becoming more common, treating patients with metastatic melanoma (MM) is still grim. The advent of immune checkpoint inhibition (ICI) therapy, particularly, has revolutionized the promise of generating more durable responses; however, the 5-year survival rate for patients with MM remains

only ~23%. Due to therapy resistance and persistence of tumor-initiating cell (TIC) subpopulations, there is a vital need for predictive biomarkers of therapeutic response and novel therapeutic targets to augment current treatments for MM. Our laboratory has recently pioneered investigations on the signature features of the

human MM cell glycome and how these discrete glycans and glycan-binding factors impact melanoma progression. The MM glycome is characterized by an abundance of cell surface i-linear poly-N- acetyllactosamines (linear poly-LacNAc) via loss of I-branching poly-LacNAc enzyme GCNT2 and elevations in LacNAc-binding lectin, galectin (Gal)-8. In fact, low melanoma cell GCNT2/I-branching corresponds with

human MM progression, whereas detection of Gal-8 in serum directly correlates with a diagnosis of melanoma. Exciting, published data show that elevations in MM cell Gal-8 and Gal-8-binding linear poly-LacNAcs directly result in expression a key TIC factor, nerve growth factor receptor (NGFR)/CD271, a known driver of therapy

resistance and MM progression. Engagement of this Gal-8 – Gal-8 ligand axis enhances TIC potential, pAKT activity, and in vivo tumor-forming activity of human MM cells. Our guiding hypothesis is that the MM glycome helps govern the malignant traits and capacity for melanomas to metastasize. Expression of

Gal-8 and its glycoprotein ligands bearing linear poly-LacNAcs may help predict which melanomas will metastasize and even provide new opportunities to treat patients with MM. In this grant, we will conduct molecular characterization of the MM cell Gal-8 – ligand axis, probe the role of Gal-8 in melanoma growth and

metastasis, and determine whether melanoma-intrinsic or host Gal-8 impacts melanoma immunity and alters anti-tumor responses to ICI therapy. The Specific Aims are: 1.) To examine the functional role of the Gal-8 – ligand axis in melanoma progression, and 2.) To analyze the growth- and metastasis-promoting roles

of Gal-8 in melanoma. We are implementing: 1.) a strong investigator team consisting of glyco-analytics experts, clinical investigators, melanoma pathologists, and galectin biology experts; 2.) primary human melanoma tissues and stage-specific melanoma patient serum samples; 3.) innovative Gal-8 ligand/glycan

assessment methods; and 4.) pre-clinical mouse and MM cell Gal-8-deficient models to impart the most impactful comprehensive data in this project. Results from this transformative proposal will illuminate how MM glycome regulates MM TIC factor, NGFR, and melanoma growth and metastasis, implicating Gal-8 and linear

poly-LacNAcs as biomarkers or therapeutic targets of MM progression.