While important clinical advances have been made in the care of patients with common malignancies, such as breast cancer, the treatment of soft tissue sarcomas has remained largely unchanged for over three decades. This lack of progress is due in part to the histological heterogeneity of human soft tissue sarcomas and the relative paucity of genomic and other analyses performed to date. Most patients with soft tissue sarcomas present with an isolated mass in the limbs, but approximately one-third will develop lung metastases and die from their disease. Because no molecular features are known to reliably predict for the development of lung metastasis, there are no molecular markers available to guide the selection of patients for systemic therapy. We hypothesize that the key molecular mechanisms of lung metastasis from soft tissue sarcomas will be conserved across vertebrate species. The goal of this proposal is to use cross- species systems genetics with human and mouse soft tissue sarcomas to identify mechanisms of lung metastasis. We will perform a comprehensive genomic analysis of mouse soft tissue sarcomas at the DNA and RNA level and use sophisticated computational analysis to compare these data to similar genomic studies from human sarcomas. We anticipate that this comparative systems genetic approach will identify molecular correlates of lung metastasis and will also reveal important mechanisms of lung metastasis. These studies will identify genomic signatures of metastasis that can be used to select individual patients with soft tissue sarcomas for systemic therapy. Moreover, new insights into mechanisms of lung metastasis may identify novel molecular targets for cancer therapy.
Project Narrative Although important advances have been made in the treatment of patients with common epithelial cancers, such as breast cancer, patients with soft tissue sarcomas have largely not benefited from the application of cancer genomics. The overall goal of this proposal is to utilize cross-species genomic analyses to identify mechanisms of lung metastasis from soft tissue sarcomas. We will perform genomic studies on sarcomas from a mouse model to identify signatures that correlate with lung metastases. Using systems genetics, we will compare the mouse genomic data with genomic studies that have been carried out on human sarcomas by our collaborators. We will validate the metastasis signatures in independent cohorts of mouse and human sarcomas. We will also generate transgenic mice to determine the mechanisms by which these genetic changes contribute to metastasis. These studies will identify genomic signatures of metastasis in human tumors that may be used to select individual patients with soft tissue sarcomas for systemic therapy. Moreover, new insights into mechanisms of lung metastasis may identify novel molecular targets for sarcoma therapy.
| Nakazawa, Michael S; Eisinger-Mathason, T S Karin; Sadri, Navid et al. (2016) Epigenetic re-expression of HIF-2? suppresses soft tissue sarcoma growth. Nat Commun 7:10539 |
| Dodd, R D; Sachdeva, M; Mito, J K et al. (2016) Myogenic transcription factors regulate pro-metastatic miR-182. Oncogene 35:1868-75 |
| Sachdeva, Mohit; Whitley, Melody J; Mito, Jeffrey K et al. (2015) MicroRNA-16 suppresses metastasis in an orthotopic, but not autochthonous, mouse model of soft tissue sarcoma. Dis Model Mech 8:867-75 |
| Sachdeva, Mohit; Dodd, Rebecca D; Huang, Zhiqing et al. (2015) Epigenetic silencing of Kruppel like factor-3 increases expression of pro-metastatic miR-182. Cancer Lett 369:202-11 |
| Eisinger-Mathason, T S Karin; Mucaj, Vera; Biju, Kevin M et al. (2015) Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis. Proc Natl Acad Sci U S A 112:E3402-11 |
| Sachdeva, Mohit; Mito, Jeffrey K; Lee, Chang-Lung et al. (2014) MicroRNA-182 drives metastasis of primary sarcomas by targeting multiple genes. J Clin Invest 124:4305-19 |
| Schönhuber, Nina; Seidler, Barbara; Schuck, Kathleen et al. (2014) A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. Nat Med 20:1340-1347 |
| Eisinger-Mathason, T S Karin; Zhang, Minsi; Qiu, Qiong et al. (2013) Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discov 3:1190-205 |
| Dodd, Rebecca D; Mito, Jeffrey K; Eward, William C et al. (2013) NF1 deletion generates multiple subtypes of soft-tissue sarcoma that respond to MEK inhibition. Mol Cancer Ther 12:1906-17 |
| Li, Zhizhong; Zhang, Yunyu; Ramanujan, Krishnan et al. (2013) Oncogenic NRAS, required for pathogenesis of embryonic rhabdomyosarcoma, relies upon the HMGA2-IGF2BP2 pathway. Cancer Res 73:3041-50 |
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