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
|
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | Correction added on 3 April 2017 after first online publication: affiliation 4 has been added for NP‐S; affiliations have been corrected from 1,2,3 to 3,4 for AN |
ISSN: | 1757-4676 1757-4684 |
DOI: | 10.15252/emmm.201506111 |