Abstract C42: DNA methyltransferase 1 (Dnmt1) is a key regulator of TGFβ-mediated endothelial-to-mesenchymal transition

Cancer-associated fibroblasts (CAFs) are prominent in the tumor microenvironment and they fuel tumor angiogenesis, tumor growth, and metastasis. CAFs are identified by smooth muscle actin and type collagen 1 expression, they promote intratumoral desmoplasia and fibrosis, and they are derived from multiple cellular precursors including tumor endothelial cells (TECs) through a TGFβ-regulated process termed endothelial-to-mesenchymal transition (EndMT). Recently, we uncovered two distinct TEC populations: TGFβ-responders that undergo rapid EndMT accompanied by CAF marker up-regulation in response to TGFβ and TGFβ non-responders that are comparatively resistant to TGFβ-induced EndMT. From a biochemical screen, we found that 5-Azacytidine, a small-molecule inhibitor of DNA methyltransferases (DNMTs), converts TGFβ non-responders into responders suggesting that TGFβ responsiveness is dictated by epigenetic mechanisms. siRNA silencing of Dnmt1 is sufficient to promote TGFb-induced EndMT in non-responders, whereas Dnmt3a or Dnmt3b are not involved. Chronic (> 7 days) TGFβ stimulation also suppresses Dnmt1 expression and drives the conversion of non-responders into responders indicating that TGFβ may un-silence CAF-specific genes in TECs in part by antagonizing DNMT1 expression/activity. Our findings shed light on the epigenetic mechanisms that regulate TGFβ- and EndMT-mediated conversion of TECs into CAFs. Targeting these mechanisms could inhibit tumor growth and spread. Citation Format: Lin Xiao, Andrew C. Dudley. DNA methyltransferase 1 (Dnmt1) is a key regulator of TGFβ-mediated endothelial-to-mesenchymal transition. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C42.