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The effect of PPARG inhibition on human angiomyolipoma cells

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 an anti-TGFb mechanism. Finally, we show striking similarity between AML cell lines and multipotent mesenchymal stromal cells (MSCs) in terms of antigen and gene expression and differentiation potential. Altogether, we establishment the first in-vivo human AML model, provide evidence that AML may originate in a PPARG-activated renal MSC lineage that is skewed towards 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94461 | GEO | 2017/02/04

SECONDARY ACCESSION(S): PRJNA369759

REPOSITORIES: GEO

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Project description: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 an anti-TGFb mechanism. Finally, we show striking similarity between AML cell lines and multipotent mesenchymal stromal cells (MSCs) in terms of antigen and gene expression and differentiation potential. Altogether, we establishment the first in-vivo human AML model, provide evidence that AML may originate in a PPARG-activated renal MSC lineage that is skewed towards 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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