PPARγ agonists enhance ET-743–induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma
Elizabeth Charytonowicz, … , Robert N. Taub, Igor Matushansky
Elizabeth Charytonowicz, … , Robert N. Taub, Igor Matushansky
Published February 1, 2012
Citation Information: J Clin Invest. 2012;122(3):886-898. https://doi.org/10.1172/JCI60015.
View: Text | PDF
Research Article Oncology

PPARγ agonists enhance ET-743–induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma

Abstract

Myxoid round cell liposarcoma (MRCLS) is a common liposarcoma subtype characterized by a translocation that results in the fusion protein TLS:CHOP as well as by mixed adipocytic histopathology. Both the etiology of MRCLS and the mechanism of action of TLS:CHOP remain poorly understood. It was previously shown that ET-743, an antitumor compound with an unclear mechanism of action, is highly effective in patients with MRCLS. To identify the cellular origin of MRCLS, we engineered a mouse model in which TLS:CHOP was expressed under the control of a mesodermally restricted promoter (Prx1) in a p53-depleted background. This model resembled MRCLS histologically as well as functionally in terms of its specific adipocytic differentiation–based response to ET-743. Specifically, endogenous mesenchymal stem cells (MSCs) expressing TLS:CHOP developed into MRCLS in vivo. Gene expression and microRNA analysis of these MSCs showed that they were committed to adipocytic differentiation, but unable to terminally differentiate. We also explored the method of action of ET-743. ET-743 downregulated TLS:CHOP expression, which correlated with CEBPα expression and adipocytic differentiation. Furthermore, PPARγ agonists enhanced the differentiation process initiated by ET-743. Our work highlights how clinical observations can lead to the generation of a mouse model that recapitulates human disease and may be used to develop rational treatment combinations, such as ET-743 plus PPARγ agonists, for the treatment of MRCLS.

Authors

Elizabeth Charytonowicz, Melissa Terry, Katherine Coakley, Leonid Telis, Fabrizio Remotti, Carlos Cordon-Cardo, Robert N. Taub, Igor Matushansky

×

Figure 3

RSG enhances ET-743–mediated adipogenesis of sarcomas in pTCp53null mice.

Options: View larger image (or click on image) Download as PowerPoint
RSG enhances ET-743–mediated adipogenesis of sarcomas in pTCp53null mice...
(A) Survival curve of p53null and pTCp53null mice receiving no treatment (NT), ET-743 (0.05 mg/kg via tail vein every 4 days), RSG (25 mg/kg via lavage daily), or both ET-743 and RSG concurrently (n = 20 per group). Treatment was initiated shortly after pathologic confirmation (tumor approximately 0.25–0.5 cm in greatest dimension) and continued until tumor was approximately 1 cm in greatest dimension or until mice showed signs of distress. On average, treatment lasted for 4–8 weeks, depending on the extent of response. All 4 survival curves for p53null mice were completely superimposable. Original magnification, ×100. (B) Quantitative RT-PCR analysis (average of 3 replicate experiments) of TLS:CHOP in p53null and pTCp53null mice, assessed at sacrifice. Values are shown relative to untreated pTCp53null group. (C) Transcriptional run-on assay from short-term single-cell suspensions (in vitro 24-hour cultures) of sarcomas from p53null and pTCp53null mice (see Methods) after in vivo treatment as in A, reflecting transcriptional activity of TLS:CHOP (from the Prx1 promoter) as well as PPARγ, CEBPα, and GADPH (from their respective endogenous promoters). (D and E) RT-PCR (average of 3 replicate experiments) of the indicated adipocytic differentiation gene set in bone marrow–derived MSCs of 8-week-old WT, p53null, and pTCp53null mice (D) or in pTCp53null mice treated as in A for 4 weeks (E). Values are shown relative to respective WT or untreated control.