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

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, belie...

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Main Authors: Hua, Tuyen N. M., Oh, Jiwoong, Kim, Sohyun, Antonio, Jayson M., Vo, Vu T. A., Om, Jiyeon, Choi, Jong-Whan, Kim, Jeong-Yub, Jung, Chan-Woong, Park, Myung-Jin, Jeong, Yangsik
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Online Access:https://animorepository.dlsu.edu.ph/faculty_research/11240
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spelling oai:animorepository.dlsu.edu.ph:faculty_research-104072023-11-08T00:48:50Z Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients Hua, Tuyen N. M. Oh, Jiwoong Kim, Sohyun Antonio, Jayson M. Vo, Vu T. A. Om, Jiyeon Choi, Jong-Whan Kim, Jeong-Yub Jung, Chan-Woong Park, Myung-Jin Jeong, Yangsik 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. 2020-04-01T07:00:00Z text https://animorepository.dlsu.edu.ph/faculty_research/11240 info:doi/10.1038/s12276-020-0413-1 Faculty Research Work Animo Repository Peroxisomes Glioblastoma multiforme—Treatment Nervous System Diseases
institution De La Salle University
building De La Salle University Library
continent Asia
country Philippines
Philippines
content_provider De La Salle University Library
collection DLSU Institutional Repository
topic Peroxisomes
Glioblastoma multiforme—Treatment
Nervous System Diseases
spellingShingle Peroxisomes
Glioblastoma multiforme—Treatment
Nervous System Diseases
Hua, Tuyen N. M.
Oh, Jiwoong
Kim, Sohyun
Antonio, Jayson M.
Vo, Vu T. A.
Om, Jiyeon
Choi, Jong-Whan
Kim, Jeong-Yub
Jung, Chan-Woong
Park, Myung-Jin
Jeong, Yangsik
Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients
description 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.
format text
author Hua, Tuyen N. M.
Oh, Jiwoong
Kim, Sohyun
Antonio, Jayson M.
Vo, Vu T. A.
Om, Jiyeon
Choi, Jong-Whan
Kim, Jeong-Yub
Jung, Chan-Woong
Park, Myung-Jin
Jeong, Yangsik
author_facet Hua, Tuyen N. M.
Oh, Jiwoong
Kim, Sohyun
Antonio, Jayson M.
Vo, Vu T. A.
Om, Jiyeon
Choi, Jong-Whan
Kim, Jeong-Yub
Jung, Chan-Woong
Park, Myung-Jin
Jeong, Yangsik
author_sort Hua, Tuyen N. M.
title Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients
title_short Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients
title_full Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients
title_fullStr Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients
title_full_unstemmed Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients
title_sort peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients
publisher Animo Repository
publishDate 2020
url https://animorepository.dlsu.edu.ph/faculty_research/11240
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