Glioblastoma multiforme (GBM) is the most common, aggressive, and deadly form of brain cancer GBM spreads rapidly and diffusely via distinct invasive processes, making it essential to investigate phenomena occurring at the tumor margins. And given the number of independent genomic mutations associated with GBM, it is critical to develop biomimetic tissue engineering approaches to directly study patient-derived biospecimens rather than generic cell lines. A major bottleneck in the field is that it remains unclear how combinations of biophysical and biomolecular signals that exist in close spatial and temporal order across the GBM tumor affect malignant phenotype and response to therapy. Spatially-patterned biomaterials capable of replicating regulatory elements of the native tumor microenvironment such as the margins are essential. We have developed a microfluidic forming technique to create libraries of optically-translucent engineered glioma biomaterials containing overlapping patterns of cell, matrix, and biomolecular cues inspired by the GBM margins. We are able to map cell response as a function of local microenvironment via multiplexed analyses of cells from discrete sub-regions of the EG via transcriptomic, secretomic, and imaging metrics. While successful for resolving clinically-relevant phenomena using immortalized cell lines, there is an acute clinical need for point-of-care tools able to gather similar information from patient-derived biospecimens. The primary objective of this application is to demonstrate a biomimetic tissue engineering approach to investigate mechanisms underlying phenotype using patient-derived biospecimens ex vivo.
Aim 1 will dissect how overlapping patterns of tumor margin-inspired signals shape malignant phenotype.
Aim 2 will define the contribution of perivascular signals on invasive phenotype.
Aim 3 will employ engineered gliomas to resolve discordances between orthotopic and heterotopic xenograft tumors via quantitative benchmarking against clinical phenotype. Engineered glioma biomaterials offer the potential for insight regarding spatial and temporal aspects of the GBM microenvironment in ways not possible with current experimental approaches. Our use of a scalable microfluidic platform as well as multiplexed assessment of GBM cells via conventional and next generation molecular analysis tools greatly reduces the size of the required patient biospecimen, accelerates the speed of analysis, and yet preserves the capability of interrogating rare cell subpopulations such as glioma cancer stem cells. Engineered glioma biomaterials have the potential to b

Public Health Relevance

Glioblastoma multiforme is the most common, aggressive, and deadly form of brain cancer. The significant spatial heterogeneity and patient-to-patient variability seen in these tumors demands new approaches that use patient-derived biospecimens, not generic cell lines, to advance our understanding of tumor growth and treatment. This project will demonstrate advanced biomaterial approaches that replicate the tumor margins to determine how the local tissue microenvironment impacts tumor growth, spreading, and therapeutic response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA197488-03
Application #
9437759
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Sorg, Brian S
Project Start
2016-03-17
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Ngo, Mai T; Harley, Brendan A C (2018) Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel. Biomaterials :
Chen, Jee-Wei Emily; Lumibao, Jan; Blazek, Audrey et al. (2018) Hypoxia activates enhanced invasive potential and endogenous hyaluronic acid production by glioblastoma cells. Biomater Sci 6:854-862
Chen, Si; Le, Thien; Harley, Brendan A C et al. (2018) Characterizing Glioblastoma Heterogeneity via Single-Cell Receptor Quantification. Front Bioeng Biotechnol 6:92
Chen, Jee-Wei E; Pedron, Sara; Shyu, Peter et al. (2018) Influence of Hyaluronic Acid Transitions in Tumor Microenvironment on Glioblastoma Malignancy and Invasive Behavior. Front Mater 5:
Chen, Jee-Wei Emily; Pedron, Sara; Harley, Brendan A C (2017) The Combined Influence of Hydrogel Stiffness and Matrix-Bound Hyaluronic Acid Content on Glioblastoma Invasion. Macromol Biosci 17:
Pedron, S; Polishetty, H; Pritchard, A M et al. (2017) Spatially graded hydrogels for preclinical testing of glioblastoma anticancer therapeutics. MRS Commun 7:442-449
Ngo, Mai T; Harley, Brendan A (2017) The Influence of Hyaluronic Acid and Glioblastoma Cell Coculture on the Formation of Endothelial Cell Networks in Gelatin Hydrogels. Adv Healthc Mater 6:
Pedron, Sara; Hanselman, Jacob S; Schroeder, Mark A et al. (2017) Extracellular Hyaluronic Acid Influences the Efficacy of EGFR Tyrosine Kinase Inhibitors in a Biomaterial Model of Glioblastoma. Adv Healthc Mater 6: