Abstract 3809: Adaptation of prostate cancer cell lines to tumor microenvironment culture conditions induces expression of androgen receptor splice variant 7 and contributes to drug resistance

Abstract

Abstract The tumor microenvironment (TME) has several characteristics that distinguish it from normal tissue, including elevated interstitial fluid pressures and hypoxic environments. Both pressurized and hypoxic culture conditions can influence gene and protein expression of tumor cells which can result in tumor metastasis and drug resistance. Enzalutamide is effective in treating metastatic castration-resistant prostate cancer (mCRPC), but majority of patients eventually develop resistance to enzalutamide. One of the biomarkers of enzalutamide resistance is the expression of androgen receptor splice variant 7 (AR-V7), but the mechanism of how AR-V7 expression is upregulated in prostate cancer is unclear. To investigate the influence of TME culture conditions on prostate cancer cell lines, 22Rv1 and LNCaP cell lines were incubated under pressurized and hypoxic culture conditions (2 PSI + 1%O2) for a minimum of 7 days. We compared cell growth, morphology changes, gene expression profiles and drug response to enzalutamide treatment. The growth of 22Rv1 and LNCaP cells was markedly inhibited under TME culture conditions, accompanied by distinct changes in cell morphology. 22Rv1 and LNCaP cells cultured under TME conditions exhibited increased resistance to enzalutamide treatment. Higher levels of AR-V7 expression were detected in 22Rv1 and LNCaP cell lines maintained for 7 days in TME culture conditions. RNA-seq data identified 700+ genes that were differentially expressed in 22Rv1 and LNCaP cell lines adapted to TME culture conditions. GSEA analysis identified signaling pathways associated with hypoxia, glycolysis and epithelial-mesenchymal transition were upregulated under TME culture conditions, and the pathways of xenobiotic metabolism and oxidative phosphorylation were downregulated by TME culture conditions. In summary, adaptation to TME culture conditions can promote the expression of AR-V7 in prostate cancer cell lines and can contribute to enzalutamide drug resistance. Adaptation of cell lines to TME culture conditions can provide meaningful insights into mechanisms of drug resistance while providing a novel approach to identify targets and biomarkers of drug resistance. Citation Format: Yunmin Li, Albert Wong, Ann Lu, James Lim. Adaptation of prostate cancer cell lines to tumor microenvironment culture conditions induces expression of androgen receptor splice variant 7 and contributes to drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3809.