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    Cancer Technologies

    (F-218) A biomaterial model to study matrix remodeling and invasion of drug-resistant glioblastoma

    Saturday, October 14, 2023
    9:30 AM – 10:30 AM PDT
    Location: Exhibit Hall - Row F - Poster # 218

      Presenting Author(s)

    • EE

      Ela Eames (she/her/hers)

      Undergraduate Researcher
      University of Illinois Urbana-Champaign
      Chicago, Illinois, United States

      • Co-Author(s)

    • VK

      Victoria Kriuchkovskaia

      Ph.D. Candidate
      University of Illinois Urbana-Champaign, United States

    • TA

      Terence Amador

      Undergraduate Researcher
      University of Illinois Urbana-Champaign, United States

      • Primary Investigator(s)

    • Brendan A.C. Harley

      Professor
      Department of Chemical and Biomolecular Engineering, University of Illinois Urbana Champaign, United States

    Introduction:: Glioblastoma (GBM), grade IV astrocytoma, is the most common and lethal form of brain cancer. Despite an aggressive treatment strategy, including maximal resection followed by radio- and chemotherapy with temozolomide (TMZ), GBM has one of the highest mortality rates among all human tumors with a median survival of only 12-15 months post diagnosis. TMZ is the standard-of-care GBM therapeutic, and GBM treatment strategy has seen no significant improvement in almost 20 years. The challenges associated with the development of new treatments/chemotherapeutics for GBM stem from multiple factors, including invasive spreading of GBM beyond surgical margins and GBM tumor microenvironment (TME) heterogeneity. This vast heterogeneity means that there are significant redundancies in invasive pathways, which pose challenges to the development of new treatments.  Furthermore, the current models used to study GBM, such as 2D assays and animal models, have their limitations.  The purpose of this study is to create a multi-factor 3D biomaterial-based model of GBM to understand these factors associated with chemotherapeutic resistance and better illustrate GBM’s invasiveness as it occurs in vivo.  

    Materials and Methods::             To understand invasiveness of GBM, a set of four isogenically matched GBM cell lines (8MGBA-WT vs. 8MGBA-TMZres, 42MGBA-WT vs. 42MGBA-TMZres) were cultured. The 8MGBA and 42MGBA cells lines were derived from female and male patients, respectively. The TMZres lines were cultured with TMZ to assure that they had an inherent resistance to TMZ, while the WT lines had no previously acquired resistance to the drug. For each cell line, 48 spheroids (5000 cells/spheroid) per cell line were created using a Corning Spheroid Microplate. 48 GelMA (methacrylamide-functionalized gelatin) hydrogels were formed per cell line, and the spheroids were manually inserted into the center of each gel. Lastly, the spheroids were observed using brightfield microscopy over the course of three days to measure the cells’ invasiveness/migration over time. This process is illustrated in Figure 1. 

    Results, Conclusions, and Discussions::


    As seen from Figure 2, an image of the spheroids over the course of three days, the cells all expanded at different rates, which were quantified using ImageJ. After analyzing the collected data, it was determined that of all the cell lines, the TMZ-resistant (8MGBA-TMZres, 42MGBA-TMZres) GBM cells display reduced motility in a three-dimensional spheroid invasion model. In addition, TMZ-resistant GBM cells display potent resistance across a broad range of physiologically relevant TMZ concentrations. This proves that acquired TMZ resistance impacts the invasiveness of GBM tumors. Additionally, Figure 3 shows the difference between invasion in a 2D model and a 3D model. The 3D model provides better differentiation (more statistical differences) between the different models, proving the 3D model’s efficacy. We have shown that a GelMA-based hydrogel platform can be successfully used to assess GBM response to TMZ in 3D cell culture. This model provides great insights into rapid tumor cell proliferation and diffusive local invasion. 




    Currently we are looking into protein depositions in the matrix, as gaining a better understanding of ECM remodeling in GBM is imperative to develop better treatments for patients. It's known that cancer cells cause abnormal deposition and stiffness of the ECM. With our 3D spheroid model, we want to study the 42MGBA pair over 7 days to look at the differences in their gene expression and cell regulating processes. We also intend to use fluorescent staining to quantify and visualize the interactions between the GBM cells and the ECM. 





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