Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target

Abstract

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane protein enriched on the cell surface of cancer cells, including melanoma, glioblastoma, and triple-negative breast cancer. There is growing evidence identifying GPNMB as a tumor-promoter; however, despite its biological and clinical significance, the molecular mechanisms engaged by GPNMB to promote tumorigenesis are not well understood. GPNMB promotes aggressive behaviors such as tumor cell proliferation, migration, and invasion. The extracellular domain of GPNMB shed from the cell surface interacts with integrins to facilitate in the recruitment of immune-suppressive and pro-angiogenic cells to the tumor microenvironment, thereby enhancing tumor migration and invasion. GPNMB also modulates receptor tyrosine kinases and integrin signaling in a cell autonomous fashion, leading to downstream kinase signaling that in turn triggers the expression and secretion of tumorigenic factors such as matrix metalloproteinases (MMPs) and cytokines. Therefore, GPNMB exerts its pro-tumorigenic role both intracellularly and in a paracrine fashion through shedding its extracellular domain. This review highlights the importance of GPNMB in cancer progression and discusses molecular mediators of GPNMB-induced tumor growth and invasion.

Keywords: Antibody-drug conjugate; Breast cancer; GPNMB; Invasion; Matrix metalloproteinase; Melanoma.

Fig. 1.

Potential pro-tumorigenic functions of GPNMB. GPNMB can exert both autocrine and paracrine effects to enhance tumor cell growth and cancer cell metastasis. GPNMB extracellular domain (ECD) is shed most likely in an ADAM10-mediated fashion. Tumor-specific integrin α5β1 interacts with the extracellular RGD domain of GPNMB to drive cancer cell metastasis by triggering the expression and secretion of tumorigenic factors such as MMPs and cytokines, most likely via the FAK/Src pathway, as well as by recruiting immune-suppressive cells (such as macrophages) to the tumor microenvironment. Crosstalk between GPNMB and Receptor Tyrosine Kinase signaling includes (1) GPNMB/NRP-1/VEGF receptor signaling that leads to increased tumor cell proliferation and invasion, (2) EGFR:GPNMB heterodimer complex formation enables interaction with LINK-A (long intergenic non-coding RNA for kinase activation, not shown) activating BRK, leading to HIF1α phosphorylation and stabilization, thereby, upregulation of its tumorigenic target genes. NRP-1, Neuropilin-1; ECD, extracellular domain/ectodomain of GPNMB; ADAM10, A Disintegrin and metalloproteinase protein 10; VEGF, Vascular endothelial growth factor; VEGFR, Vascular endothelial growth factor receptor; BRK, Breast tumor kinase or Protein-tyrosine kinase-6; HIF1α, Hypoxia-inducible factor 1-alpha.