Related Experiment Video
Updated: Jun 10, 2026
Establishment of Patient-Derived Xenograft Mouse Model with Human Osteosarcoma Tissues
Published on: March 22, 2024
Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice
Sam D Molyneux1, Marco A Di Grappa, Alexander G Beristain
1Ontario Cancer Institute, Toronto, Ontario, Canada.
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.
Insights
Researchers identified a new mouse model for osteosarcoma (OSA). Gene deletions in Prkar1a were linked to a distinct OSA subclass with RANKL overexpression, offering insights into human cancer subtypes.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Cancer classification into subclasses aids personalized therapy development.
- Identifying driver genes for molecular tumor subclasses remains challenging.
- Genomic alterations in human cancers are increasingly mapped, but clinical relevance is often unclear.
Purpose of the Study:
- To develop a novel mouse model for genomically unstable osteosarcoma (OSA) that mirrors human disease.
- To identify molecularly distinct OSA subclasses and their driver genes using integrative oncogenomics.
- To investigate the role of cAMP-dependent protein kinase type I, alpha regulatory subunit (Prkar1a) in OSA tumorigenesis.
Main Methods:
- Generation of a new mouse model for osteosarcoma.
- Integrative oncogenomic analysis to pinpoint genetic alterations.
- Mouse genetics to validate gene function in tumorigenesis.
- Analysis of human osteosarcoma samples for PRKAR1A expression.
Main Results:
- A recurrent genetic trait involving Prkar1a gene deletions at 11qE1 was identified in a distinct mouse OSA subclass.
- This subclass was characterized by RANKL overexpression.
- Prkar1a was confirmed as a bone tumor suppressor gene regulating subclass development and RANKL overexpression.
- A subset of human OSA with low PRKAR1A expression and distinct clinical behavior was uncovered.
Conclusions:
- Tumor subclasses can be recapitulated in mouse models, providing insights into human cancer.
- Prkar1a plays a critical role in osteosarcoma development and subclass determination.
- The findings support the potential for molecular stratification of human cancers based on genetic subclasses.
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