PPARG is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target
Angiomyolipoma ( AML ), the most common benign renal tumor, can result in severe morbidity from hemorrhage and renal failure. While mTORC 1 activation is involved in its growth, mTORC 1 inhibitors fail to eradicate AML , highlighting the need for new therapies. Moreover, the identity of the AML cell...
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Published in | EMBO molecular medicine Vol. 9; no. 4; pp. 508 - 530 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
John Wiley and Sons Inc
01.04.2017
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Abstract | Angiomyolipoma (
AML
), the most common benign renal tumor, can result in severe morbidity from hemorrhage and renal failure. While
mTORC
1 activation is involved in its growth,
mTORC
1 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 (
MSC
s) 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. |
---|---|
AbstractList | Angiomyolipoma (
AML
), the most common benign renal tumor, can result in severe morbidity from hemorrhage and renal failure. While
mTORC
1 activation is involved in its growth,
mTORC
1 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 (
MSC
s) 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. |
Author | Kanter, Itamar Pleniceanu, Oren Bollag, Naomi Alfandary, Hadas Shukrun, Racheli Mark‐Daniei, Michal Varda‐Bloom, Nira Vax, Einav Omer, Dorit Bar‐Lev, Dekel D Arbiser, Jack L Dekel, Benjamin Dziedzic, Klaudyna Nagler, Arnon Pode‐Shakked, Naomi Harari‐Steinberg, Orit Gnatek, Yehudit Urbach, Achia Pri‐Chen, Sara Armon, Leah Shtainfeld, Rachel Kalisky, Tomer |
AuthorAffiliation | 4 Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel 9 Winship Cancer Institute Atlanta Veterans Administration Hospital Atlanta GA USA 7 The Mina and Everard Goodman Faculty of Life Sciences Bar‐Ilan University Ramat Gan Israel 8 Department of Dermatology Emory University School of Medicine Atlanta GA USA 5 Faculty of Engineering Institute of Nanotechnology Bar‐Ilan University Ramat Gan Israel 2 Division of Pediatric Nephrology Edmond and Lily Safra Children's Hospital Sheba Medical Center Ramat Gan Israel 1 Pediatric Stem Cell Research Institute Edmond and Lily Safra Children's Hospital Sheba Medical Center Ramat Gan Israel 3 Division of Hematology and Cord Blood Bank Sheba Medical Center Ramat Gan Israel 6 Institute of Nephrology Schneider Children's Medical Center of Israel Petah Tikva Israel |
AuthorAffiliation_xml | – name: 7 The Mina and Everard Goodman Faculty of Life Sciences Bar‐Ilan University Ramat Gan Israel – name: 1 Pediatric Stem Cell Research Institute Edmond and Lily Safra Children's Hospital Sheba Medical Center Ramat Gan Israel – name: 9 Winship Cancer Institute Atlanta Veterans Administration Hospital Atlanta GA USA – name: 3 Division of Hematology and Cord Blood Bank Sheba Medical Center Ramat Gan Israel – name: 6 Institute of Nephrology Schneider Children's Medical Center of Israel Petah Tikva Israel – name: 8 Department of Dermatology Emory University School of Medicine Atlanta GA USA – name: 4 Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel – name: 2 Division of Pediatric Nephrology Edmond and Lily Safra Children's Hospital Sheba Medical Center Ramat Gan Israel – name: 5 Faculty of Engineering Institute of Nanotechnology Bar‐Ilan University Ramat Gan Israel |
Author_xml | – sequence: 1 givenname: Oren surname: Pleniceanu fullname: Pleniceanu, Oren organization: Sheba Medical Center Sheba Medical Center Sheba Medical Center Tel Aviv University – sequence: 2 givenname: Racheli surname: Shukrun fullname: Shukrun, Racheli organization: Sheba Medical Center Sheba Medical Center Tel Aviv University – sequence: 3 givenname: Dorit surname: Omer fullname: Omer, Dorit organization: Sheba Medical Center Sheba Medical Center – sequence: 4 givenname: Einav surname: Vax fullname: Vax, Einav organization: Sheba Medical Center Sheba Medical Center Tel Aviv University – sequence: 5 givenname: Itamar surname: Kanter fullname: Kanter, Itamar organization: Bar‐Ilan University – sequence: 6 givenname: Klaudyna surname: Dziedzic fullname: Dziedzic, Klaudyna organization: Sheba Medical Center Sheba Medical Center Tel Aviv University – sequence: 7 givenname: Naomi surname: Pode‐Shakked fullname: Pode‐Shakked, Naomi organization: Sheba Medical Center Sheba Medical Center Tel Aviv University – sequence: 8 givenname: Michal surname: Mark‐Daniei fullname: Mark‐Daniei, Michal organization: Sheba Medical Center Sheba Medical Center – sequence: 9 givenname: Sara surname: Pri‐Chen fullname: Pri‐Chen, Sara organization: Sheba Medical Center Sheba Medical Center – sequence: 10 givenname: Yehudit surname: Gnatek fullname: Gnatek, Yehudit organization: Sheba Medical Center Sheba Medical Center – sequence: 11 givenname: Hadas surname: Alfandary fullname: Alfandary, Hadas organization: Tel Aviv University Schneider Children's Medical Center of Israel – sequence: 12 givenname: Nira surname: Varda‐Bloom fullname: Varda‐Bloom, Nira organization: Sheba Medical Center – sequence: 13 givenname: Dekel D surname: Bar‐Lev fullname: Bar‐Lev, Dekel D organization: Sheba Medical Center Sheba Medical Center – sequence: 14 givenname: Naomi surname: Bollag fullname: Bollag, Naomi organization: Bar‐Ilan University – sequence: 15 givenname: Rachel surname: Shtainfeld fullname: Shtainfeld, Rachel organization: Bar‐Ilan University – sequence: 16 givenname: Leah surname: Armon fullname: Armon, Leah organization: Bar‐Ilan University – sequence: 17 givenname: Achia surname: Urbach fullname: Urbach, Achia organization: Bar‐Ilan University – sequence: 18 givenname: Tomer surname: Kalisky fullname: Kalisky, Tomer organization: Bar‐Ilan University – sequence: 19 givenname: Arnon surname: Nagler fullname: Nagler, Arnon organization: Sheba Medical Center Tel Aviv University – sequence: 20 givenname: Orit surname: Harari‐Steinberg fullname: Harari‐Steinberg, Orit organization: Sheba Medical Center Sheba Medical Center – sequence: 21 givenname: Jack L surname: Arbiser fullname: Arbiser, Jack L organization: Emory University School of Medicine Atlanta Veterans Administration Hospital – sequence: 22 givenname: Benjamin surname: Dekel fullname: Dekel, Benjamin email: benjamin.dekel@gmail.com, binyamin.dekel@sheba.health.gov.il organization: Sheba Medical Center Sheba Medical Center Tel Aviv University |
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Snippet | Angiomyolipoma (
AML
), the most common benign renal tumor, can result in severe morbidity from hemorrhage and renal failure. While
mTORC
1 activation is... |
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Title | PPARG is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target |
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