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

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
DOIs
StatePublished - 1 Apr 2017

Keywords

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

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