Abstract 4167: Snai2(Slug) regulates tumor angiogenesis through the induction of EndoMT

Abstract

Abstract Anti-angiogenic therapy remains an attractive option in the treatment of cancer since it has the potential to both control growth of the primary tumor and limit metastasis. However, many current anti-angiogenic cancer drugs fail to deliver long-term efficacy, likely due to adaptation of the tumor to utilize alternative angiogenic pathways. The high level of cross talk between pro-angiogenic pathways makes targeting the downstream effectors a potentially more beneficial strategy. We have recently demonstrated that the transcription factor Slug (Snai2), a master regulator of epithelial-to-mesenchymal transition (EMT), is expressed in angiogenic endothelial cells (EC) and can augment sprouting angiogenesis in vitro, likely by inducing a partial endothelial-to-mesenchymal transition (EndoMT). Slug is induced by many pro-angiogenic pathways (e.g. TGFβ, Notch, VEGF) and can directly regulate several key steps in angiogenesis, such as migration and proliferation, making it an attractive anti-angiogenic drug target. In this study we used Slug knockout mice, which are viable but runted, to test the hypothesis that Slug regulates pathological angiogenesis in vivo by inducing an EndoMT. Using a Matrigel plug assay we found that angiogenesis was reduced in Slug knockout mice compared to littermate controls. Initial analysis suggests this is the result of impaired vascular recruitment. In addition, a syngeneic subcutaneous tumor model showed that the growth of wild type tumor cells is reduced by over 50% in Slug knockout mice compared to controls. In an in vitro angiogenesis assay Slug overexpression induces hypersprouting and an increased number of disconnected cells, suggesting the complete loss of cell-cell junctions, consistent with a full EndoMT. RNA-seq comparing Slug overexpressing EC to wild type EC revealed targets that are implicated in both autocrine and paracrine regulation of tumor angiogenesis. In conclusion, these data suggest that EC expression of Slug regulates tumor angiogenesis, and that the level of slug expression may set the threshold between a partial and a full EndoMT. Citation Format: Nan Wu, Katrina Welch-Reardon, Christopher Hughes. Snai2(Slug) regulates tumor angiogenesis through the induction of EndoMT. [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 4167. doi:10.1158/1538-7445.AM2015-4167