@article{aff9d50f970044cd9e5344e95f168c64,
title = "Hyaluronic acid-functionalized gelatin hydrogels reveal extracellular matrix signals temper the efficacy of erlotinib against patient-derived glioblastoma specimens",
abstract = "Therapeutic options to treat primary glioblastoma (GBM) tumors are scarce. GBM tumors with epidermal growth factor receptor (EGFR) mutations, in particular a constitutively active EGFRvIII mutant, have extremely poor clinical outcomes. GBM tumors with concurrent EGFR amplification and active phosphatase and tensin homolog (PTEN) are sensitive to the tyrosine kinase inhibitor erlotinib, but the effect is not durable. A persistent challenge to improved treatment is the poorly understood role of cellular, metabolic, and biophysical signals from the GBM tumor microenvironment on therapeutic efficacy and acquired resistance. The intractable nature of studying GBM cell in vivo motivates tissue engineering approaches to replicate aspects of the complex GBM tumor microenvironment. Here, we profile the effect of erlotinib on two patient-derived GBM specimens: EGFR + GBM12 and EGFRvIII GBM6. We use a three-dimensional gelatin hydrogel to present brain-mimetic hyaluronic acid (HA) and evaluate the coordinated influence of extracellular matrix signals and EGFR mutation status on GBM cell migration, survival and proliferation, as well as signaling pathway activation in response to cyclic erlotinib exposure. Comparable to results observed in vivo for xenograft tumors, erlotinib exposure is not cytotoxic for GBM6 EGFRvIII specimens. We also identify a role of extracellular HA (via CD44) in altering the effect of erlotinib in GBM EGFR + cells by modifying STAT3 phosphorylation status. Taken together, we report an in vitro tissue engineered platform to monitor signaling associated with poor response to targeted inhibitors in GBM.",
keywords = "Drug resistance, Glioblastoma in vitro model, Hyaluronic acid, Hydrogel, Tumor microenvironment",
author = "Sara Pedron and Wolter, {Gabrielle L.} and Chen, {Jee Wei E.} and Laken, {Sarah E.} and Sarkaria, {Jann N.} and Harley, {Brendan A.C.}",
note = "Funding Information: The authors would like to acknowledge the members of the Roy J. Carver Biotechnology Center at the University of Illinois Urbana-Champaign for their advice and assistance with experiments for this manuscript. Specifically, the authors would like to thank Barbara Pilas in the Flow Cytometry Facility. Research reported in this publication was also supported by the National Cancer Institute ( R01CA197488 , BACH), National Institute of Diabetes and Digestive and Kidney Diseases ( R01 DK099528 , BACH), and the National Institute of Biomedical Imaging and Bioengineering ( T32EB019944 , JEC) of the National Institutes of Health . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors are also grateful for additional funding provided by the Department of Chemical & Biomolecular Engineering and the Carl R. Woese Institute for Genomic Biology at the University of Illinois at Urbana-Champaign. Funding Information: National Cancer Institute of the National Institutes of Health under Award Number R01 CA197488. National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK099528, BACH), and the National Institute of Biomedical Imaging and Bioengineering (T32EB019944, JEC) of the National Institutes of Health.The authors would like to acknowledge the members of the Roy J. Carver Biotechnology Center at the University of Illinois Urbana-Champaign for their advice and assistance with experiments for this manuscript. Specifically, the authors would like to thank Barbara Pilas in the Flow Cytometry Facility. Research reported in this publication was also supported by the National Cancer Institute (R01CA197488, BACH), National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK099528, BACH), and the National Institute of Biomedical Imaging and Bioengineering (T32EB019944, JEC) of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors are also grateful for additional funding provided by the Department of Chemical & Biomolecular Engineering and the Carl R. Woese Institute for Genomic Biology at the University of Illinois at Urbana-Champaign. Funding Information: National Cancer Institute of the National Institutes of Health under Award Number R01 CA197488 . National Institute of Diabetes and Digestive and Kidney Diseases ( R01 DK099528 , BACH), and the National Institute of Biomedical Imaging and Bioengineering ( T32EB019944 , JEC) of the National Institutes of Health . Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",
year = "2019",
month = oct,
doi = "10.1016/j.biomaterials.2019.119371",
language = "English (US)",
volume = "219",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier BV",
}