title: Lineage of origin in rhabdomyosarcoma informs pharmacological response.
abstract: Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.
authors.affiliation: Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97239, USA;
authors.forename: Jinu
authors.initials: J
authors.lastname: Abraham
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Germans Trias i Pujol Health Sciences Research Institute (IGTP), 08916 Badalona, Barcelona, Spain;
authors.forename: Yaiza
authors.initials: Y
authors.lastname: Nuñez-Álvarez
authors.affiliation: Howard Hughes Medical Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Joslin Diabetes Center, Cambridge, Massachusetts 02138, USA; Department of Pediatric Oncology, Dana Farber Cancer Institute, Division of Pediatric Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA;
authors.forename: Simone
authors.initials: S
authors.lastname: Hettmer
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Germans Trias i Pujol Health Sciences Research Institute (IGTP), 08916 Badalona, Barcelona, Spain;
authors.forename: Elvira
authors.initials: E
authors.lastname: Carrió
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
authors.forename: Hung-I Harry
authors.initials: HI
authors.lastname: Chen
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
authors.forename: Koichi
authors.initials: K
authors.lastname: Nishijo
authors.affiliation: Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97239, USA;
authors.forename: Elaine T
authors.initials: ET
authors.lastname: Huang
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
authors.forename: Suresh I
authors.initials: SI
authors.lastname: Prajapati
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland 20877, USA;
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walker
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland 20877, USA;
authors.forename: Sean
authors.initials: S
authors.lastname: Davis
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rebeles
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
authors.forename: Hunter
authors.initials: H
authors.lastname: Wiebush
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
authors.forename: Amanda T
authors.initials: AT
authors.lastname: McCleish
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
authors.forename: Sheila T
authors.initials: ST
authors.lastname: Hampton
authors.affiliation: Department of Neurology, Department of Neurological Sciences, Glenn Laboratories for the Biology of Aging, Stanford University, Palo Alto, California 94304, USA;
authors.forename: Christopher R R
authors.initials: CR
authors.lastname: Bjornson
authors.affiliation: Department of Neurology, Department of Neurological Sciences, Glenn Laboratories for the Biology of Aging, Stanford University, Palo Alto, California 94304, USA;
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Brack
authors.affiliation: Howard Hughes Medical Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Joslin Diabetes Center, Cambridge, Massachusetts 02138, USA;
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.affiliation: Department of Neurology, Department of Neurological Sciences, Glenn Laboratories for the Biology of Aging, Stanford University, Palo Alto, California 94304, USA;
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rando
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA;
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
authors.affiliation: Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA;
authors.forename: Frank C
authors.initials: FC
authors.lastname: Marini
authors.affiliation: Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Ehler
authors.affiliation: Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Zarzabal
authors.affiliation: Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
authors.forename: Martin W
authors.initials: MW
authors.lastname: Goros
authors.affiliation: Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
authors.forename: Joel E
authors.initials: JE
authors.lastname: Michalek
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland 20877, USA;
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: Department of Pathology, Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA;
authors.forename: David M
authors.initials: DM
authors.lastname: Langenau
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, Virginia 22903, USA;
authors.forename: Robin D
authors.initials: RD
authors.lastname: LeGallo
authors.affiliation: Department of Pathology, Oregon Health and Science University, Portland, Oregon 97239, USA;
authors.forename: Atiya
authors.initials: A
authors.lastname: Mansoor
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas 78229, USA; Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Germans Trias i Pujol Health Sciences Research Institute (IGTP), 08916 Badalona, Barcelona, Spain;
authors.forename: Mònica
authors.initials: M
authors.lastname: Suelves
authors.affiliation: Department of Anatomic Pathology, Department of Molecular Genetics, Taussig Cancer Center, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.affiliation: Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97239, USA;
authors.forename: Charles
authors.initials: C
authors.lastname: Keller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D018232:Rhabdomyosarcoma, Alveolar / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; C068686:Pax3 protein, mouse; C118739:entinostat
keywords: Pax3:Foxo1; alveolar rhabdomyosarcoma; histone; myoblast; sarcoma; satellite cell