Neural Stem Cell Factors as Important Players in Glioblastoma Pathogenesis

Abstract

The main goal of this PhD thesis was to understand the mechanisms underlying GBM tumor formation and progression, with a special emphasis on the study of factors that have a role in normal NSC biology, which might be providing cancer cells with the stem-like properties required to acquire tumorigenic potential.

With this purpose, this PhD thesis was divided into two different projects.

1. Transcriptional profiling of hypoxic NSC identifies calcineurin-NFATc4 signaling as a major regulator of NSC biology.

One of the main goals of our laboratory is to get a deeper understanding of NSC biology as a first step prior to applying this knowledge to the study of gliomas. Therefore, in the first project of this PhD thesis, we set out to identify novel factors that control NSC biology (whose role in NSC was previously unknown). The specific objectives of this project have been:

- Characterization of the effect of physiologic oxygen concentrations on NSC biology. - Identification of novel signaling pathways that are operative in NSC cultured under physiologic oxygen concentrations. - Identification of novel TF that orchestrate the NSC response to physiological oxygen concentrations - Functional validation of the role of NFATc4, one of the most promising candidate TF identified above on NSC properties under physiologic oxygen concentrations.

2. GPR56 is a NSC factor that restricts the proneural to mesenchymal transition in GBM by inhibiting the NF-kB pathway.

The second project was focused on the identification of factors that are involved in GBM progression from a PN to a MES subtype (PN-to-MES transition).

In a candidate-driven approach, we selected GPR56 as the focus of our studies based on its high enrichment in normal NSC as well as its function as an adhesion receptor. The main objectives of this project are listed below:

- Characterization of GPR56 expression in the adult mouse brain and during ESC differentiation into the neural lineage. - Evaluation of GPR56 expression in the different GBM subtypes and correlation with GBM subtype markers. - Functional characterization of the impact of GPR56 knockdown in GIC in vitro and in vivo. - Characterization of the role of GPR56 as an adhesion molecule in GBM. - Study of the transcriptional regulation and signaling mediators of the GPR56 pathway. - Clinical association studies between GPR56 and the GPR56-associated signature and GBM clinical features, including patient survival and MRI characteristics. - Evaluation of the expression of GPR56 and GPR56-associated signature in other tumor types beyond GBM.