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.
|Number of pages||23|
|Journal||EMBO Molecular Medicine|
|Early online date||8 Mar 2017|
|State||Published - 1 Apr 2017|
Bibliographical noteFunding Information:
BD is supported by the Ziering Foundation, the Israel Cancer Association (grant no 20150916), and the Israel Cancer Research Fund (ICRF) project grant (grant number PG-14-112). JLA is supported by the grant RO1 AR47901 and P30 AR42687 Emory Skin Disease Research Core Center Grant from the National Institutes of Health, the Robert Margolis Foundation, as well as funds from the Rabinowitch-Davis Foundation for Melanoma Research and the Betty Minsk Foundation for Melanoma Research, and the Reynolds Sarcoma Foundation. We thank Dr. Jasmin Jacob of the Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel, for her assistance with bioinformatic analysis. We also wish to express our gratitude to Prof. Iris Barshack of the Department of Pathology, Sheba Medical Center, Tel Hashomer, Israel, for providing AML histology specimens, and assistance with stainings. We dedicate this work to our beloved friend and colleague, Klaudyna Dziedzic.
© 2017 The Authors. Published under the terms of the CC BY 4.0 license
- cancer stem cells
- mesenchymal stem cells
- tuberous sclerosis complex