Abstract IA025: Using genetically engineered mouse models to study sarcoma metastasis

Abstract

Despite aggressive conventional therapy, many patients with high-risk soft-tissue sarcoma develop metastatic disease. To investigate mechanism(s) of sarcoma metastasis, our lab has utilized genetically engineered mouse models. For example, we injected an adenovirus expressing Cre recombinase (adeno-Cre) into the gastrocnemius muscle of LSL-KrasG12D; p53Flox/Flox (KP) mice to initiate high grade undifferentiated pleomorphic sarcomas, and after amputation approximately 40% of the mice develop lung metastasis. Using a genetic approach, we found that miR-182, NEAT-1, and HIF-1a regulate metastasis to the lung. We also performed lineage tracing with complementary fluorescent proteins and CRISPR-generated bar codes to find that lung metastases from KP sarcomas arise from clones with specific gene expression profiles. Although the KP sarcoma model is useful for studying metastasis, one limitation of this model is that there are few non-synonymous mutations to engage the immune system. Therefore, we generated a high mutational load primary mouse model of soft tissue sarcoma by injecting adeno-Cre into the gastrocnemius muscle of p53Flox/Flox mice to delete p53 and also injected 3-methylcholanthrene (MCA) to generate primary p53/MCA undifferentiated pleomorphic sarcomas. In this p53/MCA model, the overall rate of lung metastasis after amputation was surprisingly low (~12%). We hypothesized that the immune system suppressed lung metastasis in this model. However, when we generated p53/MCA sarcomas in Rag2 −/− mice that lack mature B and T cells, we still observed a low rate of lung metastasis after amputation. These data suggest that mutations caused by MCA may have disabled tumor intrinsic factors needed to drive sarcoma metastasis. We are currently performing genome-wide screens in the p53/MCA model to search for genes required for sarcoma metastasis. Citation Format: David G. Kirsch, Rutulkumar Patel, Sophie R. Finkelstein, Joy Ban, Yuning J Tang, Jianguo Huang, Benjamin A. Alman, Yvonne M. Mowery. Using genetically engineered mouse models to study sarcoma metastasis [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA025.