Author(s): Peyton Worley, Alma Taggart
Mentor(s): Jared Barrott
Institution BYU
Osteosarcoma(OS) is a rare and aggressive form of bone cancer affecting mainly children and adults under the age of 30. Establishing a representative transgenic murine model is essential in understanding and developing effective treatments against osteosarcomas. The previous options available for drug testing were patient-derived xenograft models and a transgenic model driven by Tp53 and Rb1 knockout alleles. The xenograft model, while they have 100% penetrance, exhibits limitations as a model because the tumor develops in an immunocompromised environment. On the other hand, this transgenic murine model exhibited limitations as a model by exemplifying a slow-growing osteosarcoma with 61% penetrance and no metastasis. We aimed to improve the transgenic model to capture the aggressive and non-responsive disease state. Forward genetic screening identified Arid1a as a key contributor to OS progression, which we hypothesized would result in an increased tumor progression and metastasis. We injected 205 total mice with tamoxifen to induce osteoblast specific recombination of tumor suppressor genes, Tp53 and Rb1, that cause osteosarcoma. 142 mice were wild type for Arid1a, 41 were homozygous knockout (KO), and 22 were heterozygous (KO/Wt). The mice were evaluated phenotypically based on penetrance, metastatic burden, and survival time. The homozygous KO Arid1a mice had 100% penetrance with 41% metastatic burden (p-value < 0.00001) and average time of survival of 7.8 months (p-value < 0.0001). The wild-type Arid1a mice had 61% penetrance, and of the mice that generated a primary tumor, a visible metastatic burden of 0% (n=84), and a survival time of 14.1 months. Our data supported our hypothesis that knockout of Arid1a leads to faster tumor progression and metastasis. In conclusion, Arid1a is a driving force in the development of aggressive and chemoresistant states of OS.