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

Tuyen N M Hua,Jiyeon Om,Sohyun Kim,Jeong-Yub Kim,Jiwoong Oh,Chan-Woong Jung,Jayson M Antonio,Myung-Jin Park,Yangsik Jeong,Jong-Whan Choi,Vu T A Vo

doi:10.1038/s12276-020-0413-1

Abstract

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 (PPARγ) as a potential diagnostic and prognostic biomarker as well as therapeutic target for MES GBM; we used multiple approaches to assess PPARγ, including biostatistics analysis and assessment of preclinical studies. First, we found that PPARγ was exclusively expressed in MES glioblastoma stem cells (GSCs), and ligand activation of endogenous PPARγ 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 PPARγ; compared to control mice, those that received ligand treatment exhibited longer survival as well as decreased tumor burden. Mechanistically, PPARγ 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 PPARγ 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 PPARγ expression was distinctly upregulated in MES GBM. Collectively, this study provides insight into PPARγ as a potential therapeutic target for patients with MES GBM.

Highlights

Glioblastoma (GBM) is the most malignant and lethal primary brain tumor in humans; GBM yields an extremely poor prognosis and quality of life that is associated with reduced cognitive function[1]
PPARγ is a pathologic diagnosis marker for MES GBM Since multiple Nuclear receptor (NR) are known to be involved in brain tumor pathogenesis[15,21,22], we wondered which subsets of NRs are associated with GBM subtypes, and we focused on PN and MES tumors
We first carried out RNA sequencing and analyzed the relative expression of 31 NRs in PN glioblastoma stem cells (GSCs), MES GSCs, normal human astrocytes (NHAs), and normal neural stem cells (NSCs)

Summary

Introduction

Glioblastoma (GBM) is the most malignant and lethal primary brain tumor in humans; GBM yields an extremely poor prognosis and quality of life that is associated with reduced cognitive function[1]. PN GBM undergoes a phenotypic shift into the more aggressive MES GBM, the so-called PMT, upon encountering diverse microenvironmental stresses, including inflammation, radiation, or chemotherapy[7,8]. It is believed that MES GBM may acquire therapeutic resistance to radiation and chemotherapy, which is responsible for tumor recurrence leading to poor prognosis[8,9]. Considering the aggressiveness of MES GBM, there is an urgent need to develop an optimal therapeutic strategy to treat devastating tumors

Methods

Results

Conclusion