Abstract 3021: Roles of EMT on stem cell properties of prostate stem and cancer cells during castration-resistant prostate cancer progression

Abstract

Abstract Androgen ablation remains the mainstay of treatment for men with advanced and metastatic prostate cancer. However, despite the introduction of new generation anti-androgens, a majority of men succumb to castration resistant prostate cancer (CRPC). The molecular mechanisms governing the emergence of treatment resistance in CRPC patients are not well understood. Recent experience suggests that tumor regeneration from castration-resistant stem-like cells induce resistance to hormonal therapy. Therefore, elucidating novel targets essential for driving stem-like activity is critical to prevent and defeat CRPC. It has been shown that normal and cancer stem cells exploit normal development process of epithelial-mesenchymal transition (EMT) to survive and metastasize, and that EMT confer stem cell properties to more differentiated cancer cell progeny in breast and other cancers. However, it is unclear if EMT is linked with stem cells in normal and malignant prostate. Our lab has reported that N-cadherin, a marker of EMT, is upregulated after neoadjuvant hormone ablation and in CRPC and is sufficient to cause metastasis and CRPC. Therapeutic targeting of N-cadherin by novel N-cadherin antibody inhibited metastatic and CRPC progression. The cell population displaying N-cadherin co-expressed a number of stem cell-associated genes in CRPC models. Here, we verified EMT linked to stem cells in both normal prostate and CRPC. We found in LAPC-9 CRPC tumors, the cell population expressing N-cadherin behaved like stem cells with enhanced sphere-forming ability, which could be specifically inhibited by novel N-cadherin antibody 2A9. We isolated stem-like CD49fhi/Trop2hi cells from prostatectomy specimens and found that forced N-cadherin expression promoted sphere formation of those cells. Our evaluation of gene expression in N-cadherin-positive prostate cancer cell lines and CRPC tumors demonstrated that N-cadherin expression activated common EMT transcriptional regulators including Zeb1. We asked if Zeb1 regulated stem cell properties in normal and malignant prostate. We found that forced Zeb1 expression induced EMT with enhanced cell invasiveness in LNCaP human prostate cancer cells. However, Zeb1 overexpression inhibited cell proliferation and CRPC tumor growth of LNCaP. Zeb1 overexpression also surprisingly inhibited sphere formation of normal stem/progenitor cells from prostatectomy specimens. Our data suggest that Zeb1-regulated EMT promotes both quiescence and invasiveness in normal and malignant prostate in which the quiescent cells may survive and play a role in treatment resistance, while N-cadherin mediates stem cell proliferation and self-renewal. Our research will likely provide useful information of EMT-related biomarkers for preventing and developing efficient therapeutics to combat the treatment resistance to new generation anti-androgens. Citation Format: Shu Lin, Evelyn Kono, Joyce Yamashiro, Sean Lee, Owen Witte, Andrew Goldstein, Robert E. Reiter. Roles of EMT on stem cell properties of prostate stem and cancer cells during castration-resistant prostate cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3021. doi:10.1158/1538-7445.AM2014-3021