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      Characterizing Glioblastoma Heterogeneity via Single-Cell Receptor Quantification

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          Abstract

          Dysregulation of tyrosine kinase receptor (RTK) signaling pathways play important roles in glioblastoma (GBM). However, therapies targeting these signaling pathways have not been successful, partially because of drug resistance. Increasing evidence suggests that tumor heterogeneity, more specifically, GBM-associated stem and endothelial cell heterogeneity, may contribute to drug resistance. In this perspective article, we introduce a high-throughput, quantitative approach to profile plasma membrane RTKs on single cells. First, we review the roles of RTKs in cancer. Then, we discuss the sources of cell heterogeneity in GBM, providing context to the key cells directing resistance to drugs. Finally, we present our provisionally patented qFlow cytometry approach, and report results of a “proof of concept” patient-derived xenograft GBM study.

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          Mechanisms and regulation of endothelial VEGF receptor signalling.

          Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are uniquely required to balance the formation of new blood vessels with the maintenance and remodelling of existing ones, during development and in adult tissues. Recent advances have greatly expanded our understanding of the tight and multi-level regulation of VEGFR2 signalling, which is the primary focus of this Review. Important insights have been gained into the regulatory roles of VEGFR-interacting proteins (such as neuropilins, proteoglycans, integrins and protein tyrosine phosphatases); the dynamics of VEGFR2 endocytosis, trafficking and signalling; and the crosstalk between VEGF-induced signalling and other endothelial signalling cascades. A clear understanding of this multifaceted signalling web is key to successful therapeutic suppression or stimulation of vascular growth.
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            Angiogenesis in brain tumours.

            Despite aggressive surgery, radiotherapy and chemotherapy, malignant gliomas remain uniformly fatal. To progress, these tumours stimulate the formation of new blood vessels through processes driven primarily by vascular endothelial growth factor (VEGF). However, the resulting vessels are structurally and functionally abnormal, and contribute to a hostile microenvironment (low oxygen tension and high interstitial fluid pressure) that selects for a more malignant phenotype with increased morbidity and mortality. Emerging preclinical and clinical data indicate that anti-VEGF therapies are potentially effective in glioblastoma--the most frequent primary brain tumour--and can transiently normalize tumour vessels. This creates a window of opportunity for optimally combining chemotherapeutics and radiation.
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                Author and article information

                Contributors
                Journal
                Front Bioeng Biotechnol
                Front Bioeng Biotechnol
                Front. Bioeng. Biotechnol.
                Frontiers in Bioengineering and Biotechnology
                Frontiers Media S.A.
                2296-4185
                11 July 2018
                2018
                : 6
                : 92
                Affiliations
                [1] 1Department of Bioengineering, University of Illinois at Urbana–Champaign , Champaign, IL, United States
                [2] 2Department of Mathematics and Department of Computer Science, University of Illinois at Urbana–Champaign , Champaign, IL, United States
                [3] 3Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana–Champaign , Urbana, IL, United States
                [4] 4Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana Champaign , Urbana, IL, United States
                [5] 5Department of Biomedical Engineering, Washington University , St. Louis, MO, United States
                Author notes

                Edited by: Paul De Vos, University Medical Center Groningen, Netherlands

                Reviewed by: Alessandro Poggi, Dipartimento delle Terapie Oncologiche Integrate, Ospedale Policlinico San Martino, Italy; Cristiana Tanase, Victor Babes National Institute of Pathology, Romania

                *Correspondence: P. I. Imoukhuede pimoukhuede@ 123456wustl.edu

                This article was submitted to Biomaterials, a section of the journal Frontiers in Bioengineering and Biotechnology

                Article
                10.3389/fbioe.2018.00092
                6050407
                30050899
                a1443920-580e-44e3-9c15-dc9c227f39b8
                Copyright © 2018 Chen, Le, Harley and Imoukhuede.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 13 March 2018
                : 21 June 2018
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 156, Pages: 12, Words: 9650
                Funding
                Funded by: National Science Foundation 10.13039/100000001
                Award ID: 1512598
                Award ID: 1653925
                Funded by: American Heart Association 10.13039/100000968
                Award ID: 16SDG26940002
                Categories
                Bioengineering and Biotechnology
                Perspective

                single-cell,glioblastoma,rtk,heterogeneity,vegfr,egfr,igfr,stem cell
                single-cell, glioblastoma, rtk, heterogeneity, vegfr, egfr, igfr, stem cell

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