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Abstract 1082: Arid1a deletion results in enhanced osteosarcomagenesis and altered chromosome structure

Osteosarcoma (OS) is a primary malignant bone tumor mainly affecting children and young adults. Early metastasis, chemoresistance and stagnation in the treatment options for the last 4 decades result in a less than 20% chance of long-term survival in metastatic OS. Investigating the molecular mechanisms underlying a more aggressive phenotype in osteosarcoma will certainly help develop novel treatment alternatives. Through a transposon-mediated forward genetic screen, we were able to increase osteosarcomagenesis by random mutagenesis. Among the possible candidate genes on our list, we discovered a loss-of-function mutation in ARID1A. ARID1A is a member of the SWI/SNF chromatin-remodeling protein complex and has been implicated as a tumor suppressor in other cancers. We hypothesized that loss of ARID1A in osteosarcoma would increase the rate of tumor progression and metastasis by impacting the epigenetic configuration of the chromatin. In-vitro (CRISPR/Cas9) deletion in human OS cell lines and cell behavioral studies validated that ARID1A loss contributes to faster tumorigenesis. To understand its effect in-vivo, we have developed mice cohorts with or without ARID1A with a Cre-mediated, Osteoblast specific (Osx) conditional knockout system. We observed that Arid1a-mutant mice develop tumors and die on an average 13 weeks earlier than that of the wildtype cohort. By 3D micro CT scanning, we further confirmed a relatively higher number of primary and metastatic tumors in the Arid1a mutant mice, albeit the histology and morphology of the tumors did not change. The analysis of genome-wide chromatin accessibility by ATAC-seq confirmed an open chromatin organization in Arid1a mutant mouse samples. We conclude that, acting as an epigenetic regulator, ARID1A plays a significant role in osteosarcoma progression and metastasis. Further investigation to strengthen this link would present the opportunity for alternatively targeting genetically unstable cancers with epigenetic drugs. Citation Format: Kaniz Fatema, Shawn Plyler, Adriene Pavek, Chris Nartker, Yanliang Wang, Kevin Jones, Jared Barrott. Arid1a deletion results in enhanced osteosarcomagenesis and altered chromosome structure [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1082.