Abstract 301: Microenvironmental regulation of epithelial-mesenchymal transitions in breast cancer metastasis.

Abstract

Abstract Metastatic spread is the main cause of death in breast cancer patients. To successfully develop metastatic lesions, tumor cells exhibit plasticity to adapt to the changing microenvironment that they encounter at both the primary and distant sites. Notably, tumor cells undergo epithelial-mesenchymal transition (EMT) to acquire metastatic potential. In the metastatic organ, the disseminated tumor cells are thought to undergo mesenchymal to epithelial transition (MET) to form lethal macrometastatic lesions. However, while EMT/MET has been well demonstrated in cancer cell lines in vitro, whether such transitions occur in vivo is debated. Our study is based on an emerging paradigm that microenvironmental regulation of epithelial-mesenchymal transitions contributes to tumor growth and metastasis. To evaluate this, we have devised a lineage tracing approach where a unique EMT-induced Cre-mediated fluorescence switch system monitors epithhelial-mesenchymal transitions in physiologically relevant orthotopic and spontaneous breast cancer metastasis in vivo. Using this system, we found that the CD11b+F4/80+ tumor-associated macrophages promote EMT in the primary tumor by secreting TGFβ1 and PDGFA, while the CD11b+Gr1+ myeloid progenitors facilitate MET of disseminated tumor cells in metastatic lungs by secreting proteoglycan versican thereby providing novel mechanistic insights into how the tumor-stroma cross talk confers prometastatic properties. Our finding that different subsets of inflammatory cells are associated with EMT in the primary tumor and MET in the metastatic organ has provided clinical translation opportunities. Previously, the therapeutic targeting of EMT (i.e. TGFβ1 blockade) has been associated with the caveat that it may actually promote the formation of fatal macrometastases. Here, the identification of unique cellular EMT and MET regulators provides an opportunity for inhibiting one process without promoting the other, or inhibiting both EMT and MET simultaneously. Importantly, administration of non-steroidal anti-inflammatory drugs impaired metastases by targeting specific inflammatory populations that contribute to the EMT/MET-promoting microenvironment in preclinical mouse models of breast cancer. Citation Format: Dingcheng Gao, Kari Fisher, Hyejin Choi, Andrew J. Dannenberg, Linda Vahdat, Nasser Altorki, Vivek Mittal. Microenvironmental regulation of epithelial-mesenchymal transitions in breast cancer metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 301. doi:10.1158/1538-7445.AM2013-301