title: 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.affiliation: Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Charytonowicz
authors.forename: Melissa
authors.initials: M
authors.lastname: Terry
authors.forename: Katherine
authors.initials: K
authors.lastname: Coakley
authors.forename: Leonid
authors.initials: L
authors.lastname: Telis
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Remotti
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Robert N
authors.initials: RN
authors.lastname: Taub
authors.forename: Igor
authors.initials: I
authors.lastname: Matushansky
mesh_terms: D017667:Adipocytes / Q000166:cytology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002454:Cell Differentiation; D004149:Dioxoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D018208:Liposarcoma, Myxoid / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009368:Neoplasm Transplantation; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D047495:PPAR gamma; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin