Abstract C112: A bad apple spoils the bunch: How environment drives tumor aggressiveness and resistance

Abstract

Abstract Glioblastoma (GBM) is the most common and aggressive type of malignant brain tumor in adults in the United States. Current treatment options at diagnosis are multimodal and include surgical resection, radiation, and chemotherapy. While the aim of combined therapy approach to GBM is long term remission, it does so in only about 20% of patients. Because the current standard GBM treatment is unlikely to result in prolonged remission, there is a great effort in Nuero-Oncology research field to better understand the oncobiology of GBM and overcome tumor resistance. GBM arises from multiple cell type with neural stem-cell proprieties (GSCs). GBM molecular profile reveled 2 predominant subtypes: proneural (PN) and mesenchymal (MES). Tumor subtype has significant prognostic value, with GBM tumors with mesenchymal signature displaying a more aggressive phenotype. Furthermore, PN tumors tend to shift toward a MES phenotype upon recurrence or after radiation therapy. Emerging evidence indicates that this phenotypic change occurs, at least in part, due to direct conversion of one cell type to another rather than selection of pre-existing therapy-resistant tumor cells. GBM grows in a rich neurochemical milieu, but the impact of neurochemicals on GBM growth is largely unexplored. Neuropeptides are a group of signaling messengers that function as neurotransmitters, paracrine regulators, and hormones to regulate exocrine and endocrine secretion and inflammation. Previously, neuropeptides have also been recognized as potent cellular growth factors for many cell types, including cancer cells. Extracellular vesicles (EVs) are critical mediators of intercellular communication between tumor cells and stromal cells in local and distant microenvironments. EVs play an essential role in both primary tumor growth and metastatic evolution. EVs contain bioactive molecules, such as nucleic acids, protein and lipids that can redirect the function of a recipient cell. Based on the regulatory function of neuropeptides we hypothesized that neuropeptides could be involved in intercellular communication between PN and MES GSCs within the tumor milieu. The aim of this project is the characterization of the neuropeptide profile of PN and MES GSCs and to investigate whether EVs could play a role in GSCs plasticity within the tumor milieu. Initially, a gene expression analysis from PN and MES GSCs was performed based on the data from a custom RNA array for human neuropeptides. After validation, five targets were selected to be tested in the intercellular communication mediated by EVs. In order to address the role of EVs in neuropeptide intercellular communication, EVs from condition medium from MES GSCs were isolated. Then, PN GSCs were treated with MES derived EVs (EVs-MES). After treatment, RNA purification was performed for real time PCR analysis. This work is the first to analyze the neuropeptide profile of GSCs. Our data show that PN and MES have a differential neuropeptide expression profile. Most interestingly is the fact that the treatment of PN cells with EVs-MES drove a shift in the neuropeptide expression in PN cells. Taking this data together we believe that neuropeptides could be one of the milieu factors linked to phenotype plasticity in GBM and could provide a new target for upcoming treatment options for GBM. Citation Format: Renata Fleming, Markus W Schweiger, Bakhos A Tannous. A bad apple spoils the bunch: How environment drives tumor aggressiveness and resistance [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C112. doi:10.1158/1535-7163.TARG-19-C112