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- Title
Arid1a Loss Enhances Disease Progression in a Murine Model of Osteosarcoma.
- Authors
Fatema, Kaniz; Wang, Yanliang; Pavek, Adriene; Larson, Zachary; Nartker, Christopher; Plyler, Shawn; Jeppesen, Amanda; Mehling, Breanna; Capecchi, Mario R.; Jones, Kevin B.; Barrott, Jared J.
- Abstract
Simple Summary: Osteosarcoma is an aggressive form of bone cancer that spreads quickly and is challenging to treat. Genetic screening in this study discovered that the loss of the Arid1a gene is a crucial factor in the development and progression of osteosarcoma. In vitro and in vivo studies validated that the loss of Arid1a increased proliferation and chemoresistance in human cell lines and led to higher disease penetrance, metastases, and shorter survival in mice. Unbiased pathway analyses suggest that Arid1a may contribute to the aggressiveness of osteosarcoma by dysregulating genomic instability. Osteosarcoma is an aggressive bone malignancy, molecularly characterized by acquired genome complexity and frequent loss of TP53 and RB1. Obtaining a molecular understanding of the initiating mutations of osteosarcomagenesis has been challenged by the difficulty of parsing between passenger and driver mutations in genes. Here, a forward genetic screen in a genetic mouse model of osteosarcomagenesis initiated by Trp53 and Rb1 conditional loss in pre-osteoblasts identified that Arid1a loss contributes to OS progression. Arid1a is a member of the canonical BAF (SWI/SNF) complex and a known tumor suppressor gene in other cancers. We hypothesized that the loss of Arid1a increases the rate of tumor progression and metastasis. Phenotypic evaluation upon in vitro and in vivo deletion of Arid1a validated this hypothesis. Gene expression and pathway analysis revealed a correlation between Arid1a loss and genomic instability, and the subsequent dysregulation of genes involved in DNA DSB or SSB repair pathways. The most significant of these transcriptional changes was a concomitant decrease in DCLRE1C. Our findings suggest that Arid1a plays a role in genomic instability in aggressive osteosarcoma and a better understanding of this correlation can help with clinical prognoses and personalized patient care.
- Subjects
OSTEOSARCOMA; BIOLOGICAL models; IN vitro studies; CANCER invasiveness; OSTEOBLASTS; CELL proliferation; IN vivo studies; CELL lines; METASTASIS; MICE; PATIENT-centered care; ANIMAL experimentation; GENETIC mutation; DISEASE progression; DNA-binding proteins; GENETIC testing; PHENOTYPES
- Publication
Cancers, 2024, Vol 16, Issue 15, p2725
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers16152725