Abstract 179: Tumor - driven extracellular matrix remodeling influences therapeutic response

Abstract

Abstract Brain cancers remain some of the most challenging tumors to treat. The goal of our research is to use a three-dimensional in vitro model to acquire in-depth understanding of the unique environment of brain tumors to find new biomarkers of disease and develop more efficient therapeutic approaches. We are interested in revealing potential associations between common genetic tumor mutations and the capacity to remodel the extracellular microenvironment. The understanding of the multiple sources of tumor heterogeneity is crucial to improve current therapeutic approaches. Glioblastomas (GBM) present a very poor prognosis, they exhibit high infiltration into brain parenchyma, impairing surgical resection and leading to recurrence. 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 (1). In this study, we investigate the influence of tumor extracellular HA in glioblastoma progression and resistance to a targeted tyrosine kinase inhibitor (erlotinib). 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 in combination with microfluidic devices (2, 3). We have found that the combinatorial treatment of anti-CD44 and erlotinib show synergistic effect in some EGFR overexpressing tumors containing HA (2). Moreover, we can investigate the signaling mechanisms associated to these phenotypic alterations. 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 (4). The MW and abundance of HA are mediated by the activity of HA synthases and hyaluronidases. HAS2 can produce very high molecular weight species and seems to play a significant role in cell invasion and cancer progression. In these HA-rich tumors we find a heterogeneous profile of MW distributions secreted by different tumor types, additionally we learnt that EGFR inhibition led to the secretion of high MW HA, associated to the upregulation of HAS2. We reveal here the importance of the tumor-associated HA biosynthesis as a mechanism of cancer cells to adapt to drug insults. The ability to manipulate tumor ECM can improve therapeutic outcomes and restrict glioblastoma growth and infiltration. (1) Monslow J. Front. Immunol. 2015; 6:231.(2) Pedron S. Adv. Healthcare Mater. 2017; 6:1700529.(3) Pedron S. MRS Commun. 2017; 7:442-449.(4) Pedron S. Biomaterials 2019; 219:119371. Citation Format: Edward R. Neves, Brendan A. Harley, Sara Pedron. Tumor - driven extracellular matrix remodeling influences therapeutic response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 179.