Abstract 1405: Macrophages induce a transcriptional program that triggers a stable epithelial to mesenchymal transition in prostate cancer cells

Abstract

Abstract Epithelial-mesenchymal transition (EMT) is a process crucial for metastatic dissemination and the acquisition of therapeutic resistance in cancer cells. Previous studies demonstrated that the interaction between macrophages and prostate cancer cells generates cells that maintain stable-EMT characteristics in culture. These cells were isolated by direct interactions between M2-type macrophages and the prostate cancer epithelial PC3-lucE cells. The EMT lines were used in mouse experiments to elucidate tumorigenic potential of the stable-EMT cells compared to the parental epithelial cells. It was found that EMT cells develop and metastasize at a faster rate than PC3-Luc-E cells when injected via an intra-cardiac injection (ICI). However, the EMT-lines grew at a similar rate than PC3 Luc-E when the cells were injected subcutaneously in mice, suggesting that the ICI results cannot be explained by the difference in the proliferation potential of the cell lines but rather their capability to survive the circulation and invade and metastasize at distant sites. The transcriptomes of three stable-EMT cell lines were compared with the parental PC3-lucE by microarray expression profiling. A shared-signature of 983 genes, which are differentially expressed in these cells compared to the parental PC3-lucE cells, was identified. The biological processes associated with this signature were determined using ‘David Bioinformatics Resources,’ and the most significant were found to correlate with macrophage-associated functions including: 1)-response to wounding (p=4.6 E-14), 2)-inflammatory response (p=3 E-10), 3)-extracellular matrix organization (p=1.1 E-9), 4)-wound healing (p=8.8 E-8) and 5)-defense response (p=1.9 E-5), as well as functions also connected to EMT: 6)-cell migration (p=5.7 E-6) and 7)-cell motility (p=1.4 E-5). Since this signature was identified in our cancer cells, it suggests that these cells through their interactions with macrophages, acquired functions that enhance matrix remodeling, cell migration, invasion, tumor progression and metastasis. Furthermore, the EMT-signature revealed the induction of a transcriptional program characterized by the up-regulation of Zeb1 and the downregulation of other transcription factors that were also regulated by ZEB1: EHF, IRF6, OVOL1/L2 and ANKRD22. Two transcription factors were identified to play a critical role in the stable EMT: ZEB1 and OVOL1. It was shown that ZEB1 knockdown or the overexpression of OVOL1 induces the reverse MET (mesenchymal-epithelial transition) in these cells suggesting a critical regulatory circuit of EMT-MET transformation in prostate cancer cells. In conclusion, macrophages do play a role in initiating EMT by inducing a transcriptional program in prostate cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1405. doi:1538-7445.AM2012-1405