Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice.
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.
Molyneux
Sam D
SD
Ontario Cancer Institute, Toronto, Ontario, Canada.
Di Grappa
Marco A
MA
Beristain
Alexander G
AG
McKee
Trevor D
TD
Wai
Daniel H
DH
Paderova
Jana
J
Kashyap
Meenakshi
M
Hu
Pingzhao
P
Maiuri
Tamara
T
Narala
Swami R
SR
Stambolic
Vuk
V
Squire
Jeremy
J
Penninger
Josef
J
Sanchez
Otto
O
Triche
Timothy J
TJ
Wood
Geoffrey A
GA
Kirschner
Lawrence S
LS
Khokha
Rama
R
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
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517835:Prkar1a protein, mouse