title: Peroxisome proliferator-activated receptor gamma (PPARγ) is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target
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 ofin vivomodels. Here, we establish a human AML-xenograft (Xn) model in mice, recapitulating AML at the histological and molecular levels. Microarray analysis demonstrated tumor growthin vivoto involve robust PPARγ-pathway activation. Similarly, immunostaining revealed strong PPARγ expression in human AML specimens. Accordingly, we demonstrate that while PPARγ agonism accelerates AML growth, PPARγ 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 firstin vivohuman AML model, which provides evidence that AML may originate in a PPARγ-activated renal MSC lineage that is skewed toward adipocytes and smooth muscle and away from osteoblasts, and uncover PPARγ as a regulator of AML growth, which could serve as an attractive therapeutic target.
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Division of Hematology and Cord Blood Bank, Sheba Medical Center, Ramat Gan, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Pleniceanu
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Racheli
authors.initials: R
authors.lastname: Shukrun
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Dorit
authors.initials: D
authors.lastname: Omer
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Einav
authors.initials: E
authors.lastname: Vax
authors.affiliation: Faculty of Engineering, Institute of Nanotechnology, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Itamar
authors.initials: I
authors.lastname: Kanter
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Klaudyna
authors.initials: K
authors.lastname: Dziedzic
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Naomi
authors.initials: N
authors.lastname: Pode-Shakked
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Mark-Daniei
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Sara
authors.initials: S
authors.lastname: Pri-Chen
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Yehudit
authors.initials: Y
authors.lastname: Gnatek
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Institute of Nephrology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Alfandary
authors.affiliation: Division of Hematology and Cord Blood Bank, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Nira
authors.initials: N
authors.lastname: Varda-Bloom
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Dekel D
authors.initials: DD
authors.lastname: Bar-Lev
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Naomi
authors.initials: N
authors.lastname: Bollag
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Shtainfeld
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Leah
authors.initials: L
authors.lastname: Armon
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Achia
authors.initials: A
authors.lastname: Urbach
authors.affiliation: Faculty of Engineering, Institute of Nanotechnology, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Tomer
authors.initials: T
authors.lastname: Kalisky
authors.affiliation: Division of Hematology and Cord Blood Bank, Sheba Medical Center, Ramat Gan, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Harari-Steinberg
authors.affiliation: Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA.|Winship Cancer Institute, Atlanta Veterans Administration Hospital, Atlanta, GA, USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel benjamin.dekel@gmail.com binyamin.dekel@sheba.health.gov.il.|Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Benjamin
authors.identifier: 0000-0002-3784-8238
authors.initials: B
authors.lastname: Dekel
mesh_terms: D018207:Angiomyolipoma / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D059630:Mesenchymal Stem Cells; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D013812:Therapeutics; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C526317:CCN2 protein, human; D047495:PPAR gamma; D020574:Proto-Oncogene Proteins c-sis; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor
keywords: angiomyolipoma; cancer stem cells; mesenchymal stem cells; tuberous sclerosis complex; PPARγ