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, α 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.


Sam D. Molyneux, Marco A. Di Grappa, Alexander G. Beristain, Trevor D. McKee, Daniel H. Wai, Jana Paderova, Meenakshi Kashyap, Pingzhao Hu, Tamara Maiuri, Swami R. Narala, Vuk Stambolic, Jeremy Squire, Josef Penninger, Otto Sanchez, Timothy J. Triche, Geoffrey A. Wood, Lawrence S. Kirschner, Rama Khokha


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