Abstract A029 Investigating the role of environmental toxicant exposures and STAG2 loss in sarcomagenesis

Abstract Humans are exposed to a variety of environmental toxicants which have been implicated in contributing to cancer development. A possible explanation for this link is that adaptive epigenetic changes occur in stem cell populations upon toxicant exposure. These cells are particularly vulnerable during developmental stages, leading to abnormal gene expression later in life. Environmental exposures have been associated with the initiation of sarcoma development. This study will focus on Ewing Sarcoma (ES), as this malignancy has a low mutational burden relative to other cancer types and is thought to be linked to agricultural chemicals. We are also focusing on stromal antigen 2 (STAG2), which is found to be frequently mutated in ES in addition to multiple other tumor types. Patients with STAG2-mutated ES have higher rates of metastatic disease and worse outcomes, but the reason for this remains poorly understood. STAG2 plays a role in the regulation of genomic organization, DNA repair, and modulation of replication stress (RS). It has also been shown that STAG2 loss may lead to dysregulation of the cGAS-STING pathway, which is critical for tumor immunosurveillance. We are testing the effects of environmental toxicants in mesenchymal stem cells (MSCs), the putative cell of origin for ES and many other sarcomas. We have successfully used CRISPR/Cas9 to generate STAG2 knockout MSCs. With this model, we are testing the effects of STAG2 loss and toxicant exposure on levels of RS, epigenomic instability, and innate immune suppression in MSCs. Our results indicate that these toxicants alter the cell cycle dynamics of MSCs, and that these alterations change depending on STAG2 status. We have also observed changes in the DNA damage response of STAG2-mutant MSCs when exposed to environmental toxicants. Interestingly, effects were seen even at sub-lethal doses that may reflect common, low-level exposures. We believe that our data will contribute to the understanding of the mechanism by which environmental toxicants facilitate malignant transformation of Ewing sarcoma and other pediatric sarcomas. Citation Format: Rachael Kohrn, Joyce Ohm. Investigating the role of environmental toxicant exposures and STAG2 loss in sarcomagenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A029.