α2,6 Sialylation mediated by ST6GAL1 promotes glioblastoma growth.

One of the least-investigated areas of brain pathology research is glycosylation, which is a critical regulator of cell surface protein structure and function. ß-Galactoside α2,6-sialyltransferase (ST6GAL1) is the primary enzyme that α2,6 sialylates N-glycosylated proteins destined for the plasma membrane or secretion, thereby modulating cell signaling and behavior. We demonstrate a potentially novel, protumorigenic role for α2,6 sialylation and ST6GAL1 in the deadly brain tumor glioblastoma (GBM). GBM cells with high α2,6 sialylation exhibited increased in vitro growth and self-renewal capacity and decreased mouse survival when orthotopically injected. α2,6 Sialylation was regulated by ST6GAL1 in GBM, and ST6GAL1 was elevated in brain tumor-initiating cells (BTICs). Knockdown of ST6GAL1 in BTICs decreased in vitro growth, self-renewal capacity, and tumorigenic potential. ST6GAL1 regulates levels of the known BTIC regulators PDGF Receptor ß (PDGFRB), Activated Leukocyte Cell Adhesion Molecule, and Neuropilin, which were confirmed to bind to a lectin-recognizing α2,6 sialic acid. Loss of ST6GAL1 was confirmed to decrease PDGFRB α2,6 sialylation, total protein levels, and the induction of phosphorylation by PDGF-BB. Thus, ST6GAL1-mediated α2,6 sialylation of a select subset of cell surface receptors, including PDGFRB, increases GBM growth.

Reactive oxygen species produced by altered tumor metabolism impacts cancer stem cell maintenance.

Controlling reactive oxygen species (ROS) at sustainable levels can drive multiple facets of tumor biology, including within the cancer stem cell (CSC) population. Tight regulation of ROS is one key component in CSCs that drives disease recurrence, cell signaling, and therapeutic resistance. While ROS are well-appreciated to need oxygen and are a product of oxidative phosphorylation, there are also important roles for ROS under hypoxia. As hypoxia promotes and sustains major stemness pathways, further consideration of ROS impacts on CSCs in the tumor microenvironment is important. Furthermore, glycolytic shifts that occur in cancer and may be promoted by hypoxia are associated with multiple mechanisms to mitigate oxidative stress. This altered metabolism provides survival advantages that sustain malignant features, such as proliferation and self-renewal, while producing the necessary antioxidants that reduce damage from oxidative stress. Finally, disease recurrence is believed to be attributed to therapy resistant CSCs which can be quiescent and have changes in redox status. Effective DNA damage response pathways and/or a slow-cycling state can protect CSCs from the genomic catastrophe induced by irradiation and genotoxic agents. This review will explore the delicate, yet complex, relationship between ROS and its pleiotropic role in modulating the CSC.

A role for GLUT3 in glioblastoma cell invasion that is not recapitulated by GLUT1.

The multifaceted roles of metabolism in invasion have been investigated across many cancers. The brain tumor glioblastoma (GBM) is a highly invasive and metabolically plastic tumor with an inevitable recurrence. The neuronal glucose transporter 3 (GLUT3) was previously reported to correlate with poor glioma patient survival and be upregulated in GBM cells to promote therapeutic resistance and survival under restricted glucose conditions. It has been suggested that the increased glucose uptake mediated by GLUT3 elevation promotes survival of circulating tumor cells to facilitate metastasis. Here we suggest a more direct role for GLUT3 in promoting invasion that is not dependent upon changes in cell survival or metabolism. Analysis of glioma datasets demonstrated that GLUT3, but not GLUT1, expression was elevated in invasive disease. In human xenograft derived GBM cells, GLUT3, but not GLUT1, elevation significantly increased invasion in transwell assays, but not growth or migration. Further, there were no changes in glycolytic metabolism that correlated with invasive phenotypes. We identified the GLUT3 C-terminus as mediating invasion: substituting the C-terminus of GLUT1 for that of GLUT3 reduced invasion. RNA-seq analysis indicated changes in extracellular matrix organization in GLUT3 overexpressing cells, including upregulation of osteopontin. Together, our data suggest a role for GLUT3 in increasing tumor cell invasion that is not recapitulated by GLUT1, is separate from its role in metabolism and survival as a glucose transporter, and is likely broadly applicable since GLUT3 expression correlates with metastasis in many solid tumors.