Abstract 1191: Targeting the tumor extracellular matrix to enhance therapeutic interventions in glioblastoma

Abstract

Abstract Brain cancers remain some of the most challenging tumors to treat. The goal of our research is to use a 3D in vitro model to acquire in-depth understanding on the unique environment of brain tumors in order to find new biomarkers of disease and develop more efficient therapeutic approaches. Brain extracellular matrix (ECM) plays a key role in glioblastoma invasion and therapeutic resistance. In particular, the aberrant biosynthesis of the main component of brain ECM, hyaluronic acid (HA), has been associated to pathological conditions. In this study, we investigate the influence of tumor extracellular microenvironment in glioblastoma progression. We focus here on the tumor-associated HA biosynthesis in response to biophysical alterations, such as hypoxia and stiffness, and after radio and chemotherapeutic interventions. The ability to manipulate tumor ECM can improve therapeutic outcomes and restrict glioblastoma growth and infiltration. We have established engineered brain tumor biomaterials based on functionalized gelatin hydrogels decorated with covalently bound HA. This biomaterial approach can monitor the response of patient-derived xenograft cell populations with different molecular signatures (1, 2) in combination with microfluidic devices. Here, we characterized tumor cell response to targeted inhibitors and ionizing radiation. We quantified HA molecular weight (MW) distribution of secreted HA, and the tumor cell response to inhibition of HA synthase 2 (HAS2) and hyaluronidase (Hyal). Analysis of HA biosynthesis suggests that GBM cells compensate for a lack of matrix-bound HA by producing soluble HA to stimulate invasion. Moreover, we revealed that different signaling pathways are altered in the tumor cells depending on the microenvironment as they respond to an EGFR and CD44 inhibitor. While the decrease in invasion and proliferation in gelatin-only matrices comes from the negative regulation of ERK pathway, HA plays a favorable role in the inhibition of EGFR, through STAT3 deactivation (3). The MW and abundance of HA are mediated by the activity of HA synthases and hyaluronidases. These enzymes vary in expression, rate, and MW of the HA produced. We have found a heterogeneous profile of MW distributions secreted by different tumor types when exposed to different targeted inhibitors. We have also shown an increase in HA secretion after exposure to radiation and inhibition of hyaluronidase, also associated to significant changes in cell proliferation. The oxidative stress induced by the hypoxic environment also induces the production of hyaluronic acid and significantly affects glycolysis and mitochondrial oxidative phosphorylation, that are further altered by the molecular weight of the HA present in the extracellular space. (1) Pedron S. Adv. Healthcare Mater. 2017; 6:1700529; (2) Pedron S. MRS Commun. 2017; 7:442-449; (3) Pedron S. Biomaterials 2019; 219:119371. Citation Format: Edward R. Neves, Joseph Mueller, Achal Anand, Kimberly A. Selting, Brendan A. Harley, Sara Pedron-Haba. Targeting the tumor extracellular matrix to enhance therapeutic interventions in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1191.