title: Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice.
abstract: Some cancers have been stratified into subclasses based on their unique involvement of specific signaling pathways. The mapping of human cancer genomes is revealing a vast number of somatic alterations; however, the identification of clinically relevant molecular tumor subclasses and their respective driver genes presents challenges. This information is key to developing more targeted and personalized cancer therapies. Here, we generate a new mouse model of genomically unstable osteosarcoma (OSA) that phenocopies the human disease. Integrative oncogenomics pinpointed cAMP-dependent protein kinase type I, alpha regulatory subunit (Prkar1a) gene deletions at 11qE1 as a recurrent genetic trait for a molecularly distinct subclass of mouse OSA featuring RANKL overexpression. Using mouse genetics, we established that Prkar1a is a bone tumor suppressor gene capable of directing subclass development and driving RANKL overexpression during OSA tumorigenesis. Finally, we uncovered evidence for a PRKAR1A-low subset of human OSA with distinct clinical behavior. Thus, tumor subclasses develop in mice and can potentially provide information toward the molecular stratification of human cancers.
authors.affiliation: Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Sam D
authors.initials: SD
authors.lastname: Molyneux
authors.forename: Marco A
authors.initials: MA
authors.lastname: Di Grappa
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Beristain
authors.forename: Trevor D
authors.initials: TD
authors.lastname: McKee
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Wai
authors.forename: Jana
authors.initials: J
authors.lastname: Paderova
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Kashyap
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Hu
authors.forename: Tamara
authors.initials: T
authors.lastname: Maiuri
authors.forename: Swami R
authors.initials: SR
authors.lastname: Narala
authors.forename: Vuk
authors.initials: V
authors.lastname: Stambolic
authors.forename: Jeremy
authors.initials: J
authors.lastname: Squire
authors.forename: Josef
authors.initials: J
authors.lastname: Penninger
authors.forename: Otto
authors.initials: O
authors.lastname: Sanchez
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Triche
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Wood
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Kirschner
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
mesh_terms: D000818:Animals; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D004195:Disease Models, Animal; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D051379:Mice; D008822:Mice, Transgenic; D012516:Osteosarcoma / Q000235:genetics*; D010641:Phenotype
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517835:Prkar1a protein, mouse