PPARG is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target

Oren Pleniceanu, Racheli Shukrun, Dorit Omer, Einav Vax, Itamar Kanter, Klaudyna Dziedzic, Naomi Pode-Shakked, Michal Mark-Daniei, Sara Pri-Chen, Yehudit Gnatek, Hadas Alfandary, Nira Varda-Bloom, Dekel D. Bar-Lev, Naomi Bollag, Rachel Shtainfeld, Leah Armon, Achia Urbach, Tomer Kalisky, Arnon Nagler, Orit Harari-SteinbergJack L. Arbiser, Benjamin Dekel

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Angiomyolipoma (AML), the most common benign renal tumor, can result in severe morbidity from hemorrhage and renal failure. While mTORC1 activation is involved in its growth, mTORC1 inhibitors fail to eradicate AML, highlighting the need for new therapies. Moreover, the identity of the AML cell of origin is obscure. AML research, however, is hampered by the lack of in vivo models. Here, we establish a human AML-xenograft (Xn) model in mice, recapitulating AML at the histological and molecular levels. Microarray analysis demonstrated tumor growth in vivo to involve robust PPARG-pathway activation. Similarly, immunostaining revealed strong PPARG expression in human AML specimens. Accordingly, we demonstrate that while PPARG agonism accelerates AML growth, PPARG antagonism is inhibitory, strongly suppressing AML proliferation and tumor-initiating capacity, via a TGFB-mediated inhibition of PDGFB and CTGF. Finally, we show striking similarity between AML cell lines and mesenchymal stem cells (MSCs) in terms of antigen and gene expression and differentiation potential. Altogether, we establish the first in vivo human AML model, which provides evidence that AML may originate in a PPARG-activated renal MSC lineage that is skewed toward adipocytes and smooth muscle and away from osteoblasts, and uncover PPARG as a regulator of AML growth, which could serve as an attractive therapeutic target.

Original languageEnglish
Pages (from-to)508-530
Number of pages23
JournalEMBO Molecular Medicine
Volume9
Issue number4
Early online date8 Mar 2017
DOIs
StatePublished - 1 Apr 2017

Bibliographical note

Publisher Copyright:
© 2017 The Authors. Published under the terms of the CC BY 4.0 license

Funding

BD is supported by the Ziering Foundation, the Israel Cancer Association (grant no 20150916), and the Israel Cancer Research Fund (ICRF) project grant (grant number PG-14-112). JLA is supported by the grant RO1 AR47901 and P30 AR42687 Emory Skin Disease Research Core Center Grant from the National Institutes of Health, the Robert Margolis Foundation, as well as funds from the Rabinowitch-Davis Foundation for Melanoma Research and the Betty Minsk Foundation for Melanoma Research, and the Reynolds Sarcoma Foundation. We thank Dr. Jasmin Jacob of the Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel, for her assistance with bioinformatic analysis. We also wish to express our gratitude to Prof. Iris Barshack of the Department of Pathology, Sheba Medical Center, Tel Hashomer, Israel, for providing AML histology specimens, and assistance with stainings. We dedicate this work to our beloved friend and colleague, Klaudyna Dziedzic.

FundersFunder number
Betty Minsk Foundation for Melanoma Research
Cancer Research Center, Sheba Medical Center
Rabinowitch-Davis Foundation for Melanoma Research
Reynolds Sarcoma Foundation
Robert Margolis Foundation
Ziering Foundation
National Institutes of Health
Israel Cancer Research FundPG-14-112, P30 AR42687, RO1 AR47901
Israel Cancer Association20150916

    Keywords

    • PPARG
    • angiomyolipoma
    • cancer stem cells
    • mesenchymal stem cells
    • tuberous sclerosis complex

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