title: Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis.
abstract: Genetic aberrations responsible for soft-tissue sarcoma formation in adults are largely unknown, with targeted therapies sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft-tissue sarcomas, resulting in elevated expression of the effector molecule Yes-Associated Protein (YAP). Based on data gathered from human sarcoma patients, a novel autochthonous mouse model, and mechanistic analyses, we determined that YAP-dependent expression of the transcription factor forkhead box M1 (FOXM1) is necessary for cell proliferation/tumorigenesis in a subset of soft-tissue sarcomas. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in coregulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of some sarcoma subtypes.
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: T S Karin
authors.initials: TS
authors.lastname: Eisinger-Mathason
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Vera
authors.initials: V
authors.lastname: Mucaj
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Biju
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Michael S
authors.initials: MS
authors.lastname: Nakazawa
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Mercy
authors.initials: M
authors.lastname: Gohil
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cash
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
authors.forename: Sam S
authors.initials: SS
authors.lastname: Yoon
authors.affiliation: INSERM U1037, Institut Claudius Regaud, 31052 Toulouse, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Skuli
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins Physical Sciences-Oncology Center, and the Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218;
authors.forename: Kyung Min
authors.initials: KM
authors.lastname: Park
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins Physical Sciences-Oncology Center, and the Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218;
authors.forename: Sharon
authors.initials: S
authors.lastname: Gerecht
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104; Howard Hughes Medical Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 celeste2@mail.med.upenn.edu.
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism* / Q000502:physiology; D000090683:Hippo Signaling Pathway; D006801:Humans; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012509:Sarcoma / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: FOXM1; Hippo; YAP; sarcoma