Glioblastoma (GBM), a uniformly lethal brain cancer, is characterized by diffuse invasion and abnormal activation of multiple receptor tyrosine kinase (RTK) signaling pathways (1). Despite current therapies, the prognosis for GBM is poor and mean survival remains less than 2 years. An improved understanding of the mechanisms driving abnormal cell signaling is essential for improving treatment outcomes. The long-term goal of this innovative proposal is to define tumor-microenvironment interactions critical in brain cancer and identify clinically relevant, druggable therapeutic targets. Specifically, we focus on the role of extracellular heparan sulfate proteoglycans (HSPGs) as they regulate the activity of multiple ligand-mediated signaling pathways (2), are altered in malignant brain tumors (3, 4), and have the potential to influence both tumor cells and critical tumor-microenvironment interactions, including the tumor-associated microglia/macrophage response. HSPGs, present on the cell surface and in the extracellular matrix, regulate signaling via their ability to bind and alter the bioavailability of diverse ligands, including growth factors, morphogens, chemokines, and enzymes. SULF2, an extracellular heparan sulfate endosulfatase, actively regulates HSPG-dependent signaling by removing the sulfate from 6-O- of glucosamine (6OS) and liberating protein ligands from HSPG sequestration (5). Alterations in HSPG core protein expression and SULF2 expression are common in diverse cancers and the PI of this proposal has shown SULF2 can drive carcinogenesis in malignant astrocytoma through regulation of RTK signaling pathways. As extracellular enzymes that are both tethered to the cell membrane and secreted, the SULFs and their HSPG substrates are present in the extracellular environment and have great potential as novel therapeutic targets.
Our Aims are:
Aim 1 : In human infiltrating astrocytomas, identify the alterations in HSPG expression and sulfation associated with tumor malignancy.
Aim 2 : Determine HSPG changes driving tumor biologic behavior, including microglia/macrophage response to tumor.
Aim 3 : Identify how HSPG alterations activate signaling pathways to promote GBM malignant behaviors. The proposed research will determine the mechanisms by which alterations in HSPGs drive oncogenic cell signaling pathways in malignant brain cancer and validate HSPGs as clinically relevant, novel therapeutic targets. Successful completion of these studies provides a preclinical basis to study agents that target HSPGs as a novel therapeutic option in malignant brain cancer.

Public Health Relevance

The mortality rates for primary malignant brain cancer have remained stable despite substantial advances in our understanding of disease biology. In the present proposal we will use innovative approaches to define how alterations in the tumor microenvironment drive oncogenic signaling pathways critical in brain cancer and identify clinically relevant, druggable therapeutic targets.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Ilkhanizadeh, Shirin; Sabelström, Hanna; Miroshnikova, Yekaterina A et al. (2018) Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma. Mol Cancer Res 16:777-790
Barnes, J Matthew; Kaushik, Shelly; Bainer, Russell O et al. (2018) A tension-mediated glycocalyx-integrin feedback loop promotes mesenchymal-like glioblastoma. Nat Cell Biol 20:1203-1214
Griveau, Amelie; Seano, Giorgio; Shelton, Samuel J et al. (2018) A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment. Cancer Cell 33:874-889.e7
Tran, Vy M; Wade, Anna; McKinney, Andrew et al. (2017) Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion. Mol Cancer Res 15:1623-1633
Miroshnikova, Yekaterina A; Mouw, Janna K; Barnes, J Matthew et al. (2016) Tissue mechanics promote IDH1-dependent HIF1?-tenascin C feedback to regulate glioblastoma aggression. Nat Cell Biol 18:1336-1345
Phillips, Joanna J; Gong, Henry; Chen, Katharine et al. (2016) Activating NRF1-BRAF and ATG7-RAF1 fusions in anaplastic pleomorphic xanthoastrocytoma without BRAF p.V600E mutation. Acta Neuropathol 132:757-760
Butowski, Nicholas; Colman, Howard; De Groot, John F et al. (2016) Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro Oncol 18:557-64
Lindberg, Olle R; McKinney, Andrew; Engler, Jane R et al. (2016) GBM heterogeneity as a function of variable epidermal growth factor receptor variant III activity. Oncotarget 7:79101-79116
Wood, Matthew D; Reis, Gerald F; Reuss, David E et al. (2016) Protein Analysis of Glioblastoma Primary and Posttreatment Pairs Suggests a Mesenchymal Shift at Recurrence. J Neuropathol Exp Neurol 75:925-935
Lemjabbar-Alaoui, Hassan; McKinney, Andrew; Yang, Yi-Wei et al. (2015) Glycosylation alterations in lung and brain cancer. Adv Cancer Res 126:305-44

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