Abstract 4666: PDX, mini-brain co-cultures and patient-derived tumor organoids: Preclinical models to study the prion protein in glioblastoma biology

Abstract

Abstract Glioblastoma (GBM), supported by a subpopulation of glioblastoma stem cells (GSCs), stands among the most harmful tumors. Its invasive and aggressive behavior has been correlated with poor therapy outcomes and reduced patient survival, which remains difficult to model and treat due to its cellular and molecular heterogeneity. GSCs are responsible for the malignant features of this cancer, including increased recurrence rates and resistance to therapy. Efforts have been employed to understand the molecular and cellular mechanisms underlying GSCs biology. The cellular prion protein (PrPC), encoded by the PRNP gene, is a key player in GBM biology, and our group has proposed PrPC as a scaffold protein that integrates signaling platforms involved in GSCs maintenance. A deeper understanding of the intracellular pathways modulated by PrPC is essential to identify novel targets for GBM treatment. We have analyzed bulk-RNA sequencing (RNA-seq) data from patient-derived xenografts (PDX) and in vitro preclinical experimental models. RNA-seq analyses identified differentially expressed genes (DEGs) associated with adhesion and migration signaling pathways in PDX cells with high PRNP expression (PRNP−HIGH). Morphological characterization of PDX samples with PRNP−HIGH levels showed an increase in morphologically undifferentiated cell groups, that are more commonly found in younger GBM patients. Furthermore, molecular profiling using Exome data showed that groups PRNP−HIGH present enhanced global patterns of gene mutations. Due to the importance of experimental models to translate basic science into clinical applications, we are establishing emerging models to study PrPC function in GBM biology: glioblastoma organoids (GBO) from patient’s surgically resected GBM tumors; and brain organoids derived from human-induced pluripotent stem cells. We noticed a morphological and molecular reproducibility of the cytoarchitecture of brain organoids and GBO, similar to that described in the literature, indicating consistency in 3D structures, despite the variability between patients. Furthermore, brain organoids will be co-cultured with GSCs, providing platforms for studying the interaction between tumor cells and brain parenchyma. The establishment of these models will improve our comprehension of the role of PrPC in GSCs maintenance and provide additional tools to understand GBM biology and predict tumor progression and response to treatment. Citation Format: Maria Clara da Silva Souza, Barbara P. Coelho, Camila F. Fernandes, Tiago G. Dos Santos, Stefan Knorst, Cibele Masotti, Maria Rita S. Passos-Bueno, Marilene H. Lopes. PDX, mini-brain co-cultures and patient-derived tumor organoids: Preclinical models to study the prion protein in glioblastoma biology. [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 4666.