TY - JOUR
T1 - Extracellular Hyaluronic Acid Influences the Efficacy of EGFR Tyrosine Kinase Inhibitors in a Biomaterial Model of Glioblastoma
AU - Pedron, Sara
AU - Hanselman, Jacob S.
AU - Schroeder, Mark A.
AU - Sarkaria, Jann N.
AU - Harley, Brendan A.C.
N1 - Funding Information:
The authors would like to acknowledge Dr. Mayandi Sivaguru and Dr. Kingsley Boateng (IGB, UIUC) for assistance with fluorescence imaging and immunohistochemistry and Gabrielle Wolter for assistance with Western Blot analyses. The authors are grateful for seed funding provided by the Illini 4000 as well as the by Mayo Clinic – University of Illinois Alliance for Technology-Based Healthcare. Research reported in this publication was also supported by the National Cancer Institute of the National Institutes of Health under Award Number R01 CA197488. 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. Figure 3 has been adopted November 8th, 2017, after previous online publication.
Funding Information:
The authors would like to acknowledge Dr. Mayandi Sivaguru and Dr. Kingsley Boateng (IGB, UIUC) for assistance with fluorescence imaging and immunohistochemistry and Gabrielle Wolter for assistance with Western Blot analyses. The authors are grateful for seed funding provided by the Illini 4000 as well as the by Mayo Clinic ? University of Illinois Alliance for Technology-Based Healthcare. Research reported in this publication was also supported by the National Cancer Institute of the National Institutes of Health under Award Number R01 CA197488. 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. Figure has been adopted November 8th, 2017, after previous online publication.
Publisher Copyright:
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2017/11/8
Y1 - 2017/11/8
N2 - 3D biomaterial models have potential to explore the influence of the tumor microenvironment on aberrant signaling pathways and compensatory signals using patient-derived cells. Glioblastoma (GBM) tumors are highly heterogeneous, with both cell composition and extracellular matrix biophysical factors seen as key regulators of malignant phenotype and treatment outcomes. Amplification, overexpression, and mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase have been identified in 50% of GBM patients. Here, hyaluronic acid (HA) decorated methacrylamide-functionalized gelatin (GelMA) hydrogels are used to examine the synergies between microenvironmental factors and a model EGFR tyrosine kinase inhibitor (TKI) using patient-derived xenograft cells. The in vitro behavior of 3 patient-derived xenografts that reflect a clinically relevant range of EGFR variants is characterized: GBM10 (EGFR, wild type), GBM12 (EGFR+), and GBM6 (EGFRvIII). GelMA hydrogels support xenograft culture; cells remain viable, active, respond to matrix-immobilized HA, and upregulate genes associated with matrix remodeling and tumor growth. Interestingly, matrix-immobilized HA alters the response of GBM cells to a model tyrosine kinase inhibitor, erlotinib. While constitutively activated EGFRvIII cells are sensitive to TKI in gelatin hydrogels, hyaluronic acid mediated adhesive signaling interacts with EGFRvIII signaling to increase cell metabolic activity, increase soluble hyaluronic acid synthesis, and modify response to erlotinib exposure.
AB - 3D biomaterial models have potential to explore the influence of the tumor microenvironment on aberrant signaling pathways and compensatory signals using patient-derived cells. Glioblastoma (GBM) tumors are highly heterogeneous, with both cell composition and extracellular matrix biophysical factors seen as key regulators of malignant phenotype and treatment outcomes. Amplification, overexpression, and mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase have been identified in 50% of GBM patients. Here, hyaluronic acid (HA) decorated methacrylamide-functionalized gelatin (GelMA) hydrogels are used to examine the synergies between microenvironmental factors and a model EGFR tyrosine kinase inhibitor (TKI) using patient-derived xenograft cells. The in vitro behavior of 3 patient-derived xenografts that reflect a clinically relevant range of EGFR variants is characterized: GBM10 (EGFR, wild type), GBM12 (EGFR+), and GBM6 (EGFRvIII). GelMA hydrogels support xenograft culture; cells remain viable, active, respond to matrix-immobilized HA, and upregulate genes associated with matrix remodeling and tumor growth. Interestingly, matrix-immobilized HA alters the response of GBM cells to a model tyrosine kinase inhibitor, erlotinib. While constitutively activated EGFRvIII cells are sensitive to TKI in gelatin hydrogels, hyaluronic acid mediated adhesive signaling interacts with EGFRvIII signaling to increase cell metabolic activity, increase soluble hyaluronic acid synthesis, and modify response to erlotinib exposure.
KW - EGFR
KW - glioblastoma
KW - hyaluronan
KW - patient-derived tumor cells
KW - tumor microenvironment
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U2 - 10.1002/adhm.201700529
DO - 10.1002/adhm.201700529
M3 - Article
C2 - 28766870
AN - SCOPUS:85026627070
SN - 2192-2640
VL - 6
JO - Advanced healthcare materials
JF - Advanced healthcare materials
IS - 21
M1 - 1700529
ER -