Hypoxia controls the glycome signature and galectin-8 – ligand axis to promote pro-tumorigenic properties of metastatic melanoma.
Chakraborty A, Perez M, Carroll JD, Antonopoulos A, Dell A, Ortega L, Mohammed NBB, Wells M, Staudinger C, Griswold A, Chandler KB, Marrero C, Jimenez R, Tani Y, Wilmott JS, Thompson JF, Wang W, Sackstein R, Scolyer RA, Murphy GF, Haslam SM, Dimitroff CJ. J Invest Dermatol. 2022 Sep 26:S0022-202X(22)01931-5. doi: 10.1016/j.jid.2022.07.033. Epub ahead of print. PMID: 36174713.
The prognosis for patients with metastatic melanoma (MM) involving distant organs is grim, and treatment resistance is potentiated by tumor-initiating cells (TIC) that thrive under hypoxia. MM cells, including TICs, express a unique glycome featuring i-linear poly-N-acetyllactosamines (poly-LacNAc) via loss of I-branching enzyme, β1,6 N-acetylglucosaminyltransferase 2 (GCNT2). Whether hypoxia instructs MM TIC development by modulating the glycome signature remains unknown. Here, we explored hypoxia-dependent alterations in MM glycome-associated genes and found that GCNT2 was downregulated and a galectin (Gal)-8 – ligand axis, involving both extracellular and cell-intrinsic Gal-8, was induced. Low GCNT2 levels correlated with poor patient outcome and patient serum samples were elevated for Gal-8. Depressed GCNT2 in MM cells upregulated TIC marker, nerve growth factor receptor (NGFR)/CD271, whereas loss of MM cell-intrinsic Gal-8 markedly lowered NGFR and reduced TIC activity in vivo. Extracellular Gal-8 bound preferentially to i-linear poly-LacNAcs on N-glycans of the TIC marker and pro-metastatic molecule CD44, among other receptors and activated pro-survival factor AKT. This study reveals the importance of hypoxia governing the MM glycome by enforcing i-linear poly-LacNAc and Gal-8 expression. This mechanistic investigation also uncovers glycome-dependent regulation of pro-MM factor, NGFR, implicating i-linear poly-LacNAcs and Gal-8 as biomarkers and therapeutic targets of MM.