Abstract 5224: Non-canonical activity of threonyl-tRNA synthetase promotes angiogenesis and invasion in a mouse model of ovarian cancer

Abstract

Despite clear connections between the tumor microenvironment and ovarian cancer invasion, the underlying molecular mechanisms remain elusive. We have recently shown that the protein synthesis regulator threonyl-tRNA synthetase (TARS) has a unique extracellular angiogenic activity separate from its canonical function. Secreted TARS promotes endothelial cell migration and tube formation, and a selective TARS inhibitor, BC194, disrupts normal vessel development in zebra fish and chick embryo models. TARS expression also correlates with tumor stage and angiogenesis in human ovarian cancer. The objective of this study was to validate the biological and clinical relationship between TARS and ovarian tumor progression using a syngenic mouse model of epithelial ovarian cancer. Tumors were initiated by intraperitoneal injection of ID8 mouse ovarian cancer cells, and tumors formed at 4-6 weeks were scored for invasiveness and analyzed by immunostaining for TARS expression and microvascular density. To test the hypothesis that overexpression of TARS promotes invasion, cells were stably transfected with a TARS expression plasmid prior to injection. To test the hypothesis that TARS inhibition reduces tumor invasion, animals harboring ID8 tumors were treated with the high-affinity TARS inhibitor BC194. We found that TARS levels were elevated in ovarian tumors as compared with normal ovarian tissue. Overexpression of TARS in ID8 cells also resulted in enhanced invasiveness and microvascular density of the resulting tumors (p = 0.026). Preliminary results also indicated that inhibition of TARS by BC194 treatment reduced tumor angiogenesis and growth (p = 0.005) without observed toxicities in the animals. Overall, these results show that modifying TARS expression or activity can affect in vivo ovarian tumor angiogenesis and progression. These results encourage further study of TARS as a regulator of the tumor microenvironment and as a possible target for diagnosis and treatment of ovarian cancer. Citation Format: Peibin Wo, Theresa Wellman, Alan Howe, Christopher Francklyn, Karen M. Lounsbury. Non-canonical activity of threonyl-tRNA synthetase promotes angiogenesis and invasion in a mouse model of ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5224. doi:10.1158/1538-7445.AM2015-5224