Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice
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
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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Research Article Oncology

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, 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.

Authors

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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Figure 3

MOTO tumors exhibit genomic instability and PKA subunit gene CNAs.

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MOTO tumors exhibit genomic instability and PKA subunit gene CNAs. (A) R...
(A) Representative metaphase from SKY analysis of a MOTO tumor, displaying near tetraploid karyotype. (B) Nonrecurrent structural chromosomal aberrations in a primary tumor (top row), cell line (moto1.1; bottom row, left), and lung metastasis (bottom row, middle and right). (C) High-resolution aCGH on 14 MOTO OSA tumors and 3 moto cell lines. Data plotted are the aberration frequency across the autosomal chromosomes; chromosomes X and Y are not shown. Red bars indicate copy number gains; green bars indicate copy number losses. Each numbered segment along the x axis defines a block of data, corresponding to the indicated autosomal chromosome. (D) Integrative DNA-RNA analysis of sample-matched OSA shows concurrent deletion/underexpression of Prkar1a at 11qE1 or (E) focal amplification/overexpression of Prkaca at 8qC3. Top and middle panels contain frequency plots for CNAs and representative aCGH probe level aberration plots for the enlarged regions in question. Bottom panels show heat maps for the expression of genes within each region normalized to WT bone (black arrows indicate Prkar1a and Prkaca). Colored rectangles in D and E indicate the type of PKA CNA for each sample (green indicates Prkar1a deletion; red indicates Prkaca amplification; and gray indicates no PKA subunit gene CNA).