Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients

Abstract

Brain cancer: Nuclear receptor offers diagnostic and therapeutic target A protein that helps relay signals within tumor cells provides a promising diagnostic biomarker and therapeutic target for the most deadly form of glioblastoma, a brain cancer. A research team in South Korea led by Myung-Jin Park from the Korea Institute of Radiological and Medical Sciences in Seoul and Yangsik Jeong from Yonsei University in Wonju showed that the gene encoding a nuclear receptor protein called PPAR gamma is exclusively expressed in glioblastoma stem cells taken from patients with the aggressive "mesenchymal" subtype of the disease, but not in stem cells from other glioblastomas with more favorable outcomes. In cell cultures and mouse models, the researchers found that elevated levels of the nuclear receptor promote cancer growth, but activation of PPAR gamma, either with drugs or by genetic means, has an opposite effect and suppresses tumor proliferation. Glioblastomas (GBMs) are characterized by four subtypes, proneural (PN), neural, classical, and mesenchymal (MES) GBMs, and they all have distinct activated signaling pathways. Among the subtypes, PN and MES GBMs show mutually exclusive genetic signatures, and the MES phenotype is, in general, believed to be associated with more aggressive features of GBM: tumor recurrence and drug resistance. Therefore, targeting MES GBMs would improve the overall prognosis of patients with fatal tumors. In this study, we propose peroxisome proliferator-activated receptor gamma (PPAR gamma) as a potential diagnostic and prognostic biomarker as well as therapeutic target for MES GBM; we used multiple approaches to assess PPAR gamma, including biostatistics analysis and assessment of preclinical studies. First, we found that PPAR gamma was exclusively expressed in MES glioblastoma stem cells (GSCs), and ligand activation of endogenous PPAR gamma suppressed cell growth and stemness in MES GSCs. Further in vivo studies involving orthotopic and heterotopic xenograft mouse models confirmed the therapeutic efficacy of targeting PPAR gamma; compared to control mice, those that received ligand treatment exhibited longer survival as well as decreased tumor burden. Mechanistically, PPAR gamma activation suppressed proneural-mesenchymal transition (PMT) by inhibiting the STAT3 signaling pathway. Biostatistical analysis using The Cancer Genomics Atlas (TCGA, n = 206) and REMBRANDT (n = 329) revealed that PPAR gamma upregulation is linked to poor overall survival and disease-free survival of GBM patients. Analysis was performed on prospective (n = 2) and retrospective (n = 6) GBM patient tissues, and we finally confirmed that PPAR gamma expression was distinctly upregulated in MES GBM. Collectively, this study provides insight into PPAR gamma as a potential therapeutic target for patients with MES GBM.