title: PPARγ agonists promote differentiation of cancer stem cells by restraining YAP transcriptional activity.
abstract: Osteosarcoma (OS) is a highly aggressive pediatric bone cancer in which most tumor cells remain immature and fail to differentiate into bone-forming osteoblasts. However, OS cells readily respond to adipogenic stimuli suggesting they retain mesenchymal stem cell-like properties. Here we demonstrate that nuclear receptor PPARγ agonists such as the anti-diabetic, thiazolidinedione (TZD) drugs induce growth arrest and cause adipogenic differentiation in human, mouse and canine OS cells as well as in tumors in mice. Gene expression analysis reveals that TZDs induce lipid metabolism pathways while suppressing targets of the Hippo-YAP pathway, Wnt signaling and cancer-related proliferation pathways. Significantly, TZD action appears to be restricted to the high Sox2 expressing cancer stem cell population and is dependent on PPARγ expression. TZDs also affect growth and cell fate by causing the cytoplasmic sequestration of the transcription factors SOX2 and YAP that are required for tumorigenicity. Finally, we identify a TZD-regulated gene signature based on Wnt/Hippo target genes and PPARγ that predicts patient outcomes. Together, this work highlights a novel connection between PPARγ agonist in inducing adipogenesis and mimicking the tumor suppressive hippo pathway. It also illustrates the potential of drug repurposing for TZD-based differentiation therapy for osteosarcoma.
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY, USA.
authors.forename: Upal
authors.initials: U
authors.lastname: Basu-Roy
authors.affiliation: Perlmutter Cancer Center, Langone Medical Center, New York, NY, USA.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Han
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY, USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Rattanakorn
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY, USA.
authors.forename: Abhilash
authors.initials: A
authors.lastname: Gadi
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY, USA.
authors.forename: Narendra
authors.initials: N
authors.lastname: Verma
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY, USA.
authors.forename: Giulia
authors.initials: G
authors.lastname: Maurizi
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA.
authors.forename: Preethi H
authors.initials: PH
authors.lastname: Gunaratne
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Department of Orthopaedic Surgery, NYU School of Medicine, New York, NY, USA.
authors.forename: Oran D
authors.initials: OD
authors.lastname: Kennedy
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY, USA.|Perlmutter Cancer Center, Langone Medical Center, New York, NY, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY, USA.|Perlmutter Cancer Center, Langone Medical Center, New York, NY, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Basilico
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY, USA.|Perlmutter Cancer Center, Langone Medical Center, New York, NY, USA.
authors.forename: Alka
authors.initials: A
authors.lastname: Mansukhani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology; D050156:Adipogenesis; D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004285:Dogs; D000090683:Hippo Signaling Pathway; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000737:chemistry; D014157:Transcription Factors; D051153:Wnt Proteins / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D047495:PPAR gamma; D010750:Phosphoproteins; D045162:Thiazolidinediones; D014157:Transcription Factors; D051153:Wnt Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; D000077154:Rosiglitazone; D017346:Protein Serine-Threonine Kinases
keywords: adipocyte; cancer stem cells; osteoblast lineage; osteosarcoma; thiazolidinediones