Abstract 3402: Castration resistance transcriptome in prostate cancer revealed by single-cell RNA-seq
Authors: Horning Aaron M. , Lin Che-Kuang , Wang Yao , Lieberman Brandon , Mahalingam Devalingam , Gao Ming , Wang Pei , Wang Chiou-Miin , Liu Zhijie , Ruan Jianhua , Liss Michael A. , Jin Victor X. , Huang Tim H-M , Chen Chun-Liang 
Published: August 2018

Abstract
Fatal metastatic castration-resistant prostate cancer (mCRPC) remains without sensitive early detection biomarkers and effective therapeutic targets. Among 2.5 millions of prostate cancer patients, the majority will face a dilemma, to treat or not to treat, at a point as cancer progresses. Biomarkers for mRCPC at an early stage represent an unmet need. With early identification, clinicians could design new treatment strategies to reduce metastasis-related morbidity and to extend survival of patients. In this study, we deployed single-cell RNA-seq on prostate cancer cells (LNCaP, ABL and PC3) to determine the transcriptome in androgen independency and castration resistance of prostate cancer. We identified potential 336 androgen-independence specific genes and 2396 castration resistance specific genes in ABL and PC3 cells respectively, while only 136 genes were shared in both cells. These genes, mostly upregulated were enriched in 43 and 166 signaling pathways that implicated the complexity of the castration resistance transcriptomic systems and networks. The signaling pathways are involved in advanced and metastatic malignancies including WNT, TGFB, ITGA/B, STAT, EPH, focal adhesion, adherens junction, regulation of actin cytoskeleton, gap junction, tight junction and EMT. Malignant potencies of ~ 40 pathways were validated by in silico analysis of the RNA-seq data from the prostate cancer cohort of The Cancer Genomic Atlas (TCGA) using Kaplan-Meier disease free and survival curve analyses. The transcriptomic regulation of these genes was further validated and correlated with ATAC-seq data. In order to further verify the functions of those signaling pathways in castration resistance, 9 major signaling pathways were evaluated using small molecule inhibitors. Castration resistant prostate cancer cells showed significant defective cell proliferation, migration, invasion and sphere formation in the presence of inhibitors, whereas LNCaP and ABL cells displayed limited or non-significant changes. Interestingly, 4 small molecule inhibitors showed significant suppression on the growth of stem-like circulating tumor cells that were derived from clinical blood samples of prostate cancer patients. Our data suggest that those castration resistance specific genes and signaling pathways revealed by single-cell RNA-seq may serve as potential markers and therapeutic targets.
Citation Format: Aaron M. Horning, Che-Kuang Lin, Yao Wang, Brandon Lieberman, Devalingam Mahalingam, Ming Gao, Pei Wang, Chiou-Miin Wang, Zhijie Liu, Jianhua Ruan, Michael A. Liss, Victor X. Jin, Tim H-M Huang, Chun-Liang Chen. Castration resistance transcriptome in prostate cancer revealed by single-cell RNA-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3402.