Elucidating the role of Perilipin-2-mediated lipid droplet formation in supporting glioblastoma pathogenesis

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Glioblastoma is the most common and aggressive form of malignant brain tumor in adults, for which novel and more efficient therapies are warranted. The microenvironment of glioblastoma is characterized by high levels oxidative stress, which exerts a selective pressure on tumor cells to form adaptive mechanisms to these adverse conditions. Ultimately, this may result in the selection of more aggressive tumor subclones that are resistant to radio/chemotherapy, whose mechanisms of action rely on the induction of oxidative stress. Thus, understanding the molecular adaptations of glioblastoma cells to oxidative stress could potentially reveal vulnerabilities that can be targeted therapeutically. It has recently been described that one aspect of lipid metabolism- the formation of lipid droplets, serves a pro-tumorigenic function in many cancers including glioblastoma. However, the mechanisms underlying this function are not described. Notably, we discovered that established human glioblastoma cell lines contained high levels of lipid droplets. In parallel, we observed that the gene encoding an essential lipid droplet coat protein, Perilipin-2 (PLIN2) was significantly upregulated in tumor tissue from multiple cohorts of glioma and glioblastoma patients, as compared to normal brain tissue. More significantly, preliminary analyses of these public databases revealed that high levels of PLIN2 expression was correlated with poorer overall survival in glioblastoma patients, suggesting that PLIN2 was a clinically relevant factor for poor prognosis. Our preliminary findings also showed that PLIN2 might play a role in the adaptation of tumor cells to oxidative stress, since treatment of these cells with exogenous oxidative stress increased both PLIN2 expression and number of lipid droplets, while knockdown of PLIN2 expression sensitized cells to such treatment. Here, we propose to study in detail the biological function and clinical relevance of PLIN2-mediated lipid droplets in GBM. First, we will determine how PLIN2-mediated lipid droplets support glioblastoma tumorigenicity in vitro, and elucidate the precise molecular mechanisms by which they protect glioblastoma cells against oxidative stress. Second, we will delineate the molecular pathways that govern the transcriptional regulation of PLIN2 in glioblastoma cells. Third, we will further explore the clinical relevance of PLIN2 by assessing the potential association between its expression and clinical parameters of large prospective cohorts of glioblastoma patients, as well as the clinical relevance of lipid droplets according to intra-tumor regional heterogeneity. Overall, the proposed project is expected to significantly contribute to our understanding of the role of lipid droplets in the pathogenicity of glioblastoma, and may potentially lead to the uncovering of PLIN2 as a promising therapeutic target.