Abstract 4065: Delineating the role of epithelial-mesenchymal transition in the generation and maintenance of prostate cancer stem cells

Abstract

Abstract Prostate cancer cells depend on androgens for growth and survival. While androgen-deprivation-therapy (ADT) results in regression of the tumor bulk, in many cases, the cancers recur in aggressive androgen-independent forms that are also resistant to standard-of-care therapies. The prevailing hypothesis is that pre-existing androgen-independent prostate cancer (PCa) stem-cells in the primary tumor are selectively enriched following therapy. However, we have previously shown that induction of epithelial-mesenchymal-transition (EMT) in differentiated breast epithelial cells can result in the generation of cells with stem-cell properties. In the current study, we investigated if induction of EMT in PCa promotes stem-cell features and androgen-receptor (AR) regulation, and if targeting EMT-promoting pathways renders PCa stem-cells sensitive to ADT. We found that LNCaP-PSAlow cells, which were previously shown to represent the PCa stem-cell population, exhibit EMT properties. Induction of EMT through over-expression of EMT-inducing transcription factors or with TGFβ1 treatment, significantly stimulated stem-cell properties in the androgen-sensitive LNCaP cells, whereas inhibition of EMT in the androgen-insensitive DU145 cells using targeted shRNA or a specific TGFβ1-signaling inhibitor, resulted in markedly reduced stemness. We observed that FOXC2 expression consistently correlated with induction of EMT and androgen-insensitivity in PCa cells. Our study demonstrates that targeting EMT-inducing molecules and signaling pathways could represent a tangible approach to inhibiting the generation and maintenance of therapy-resistant PCa stem-cells, that are the prime harbingers of tumor recurrence. Citation Format: Anurag N. Paranjape, Rama Soundararajan, Steven J. Werden, Robiya Joseph, Joseph H. Taube, Neeraja Bhangre, Hui Liu, Jaime Rodriguez-Canales, Ignacio I. Wistuba, Jeffrey T. Chang, Dean G. Tang, Nupam Mahajan, Kiran Mahajan, Naoyuki Miura, Sendurai A. Mani. Delineating the role of epithelial-mesenchymal transition in the generation and maintenance of prostate cancer stem cells. [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 4065. doi:10.1158/1538-7445.AM2015-4065