Abstract 2703: Bioinformatics approaches to dissecting androgen receptor activity and cancer stemness during prostate cancer development and progression

Abstract

Abstract Background: Cancer progression is generally accompanied by loss of differentiation and gain of stemness features. In prostate cancer (PCa), androgen receptor (AR) signaling at the transcription level has been reported to decline in high-grade vs. low-grade tumors. Also, loss of AR expression promotes a stem-like cell phenotype, implicating inverse relationship between AR signaling and stemness in PCa. Here, we aim to understand the dynamic changes in stem-like features and AR signaling activity (AR-A) at the global transcriptomic level, and the relationship between the AR-A and stemness, across the spectrum of PCa development and progression. Methods: We adapted and developed bioinformatic pipelines to assess the degree of cancer stemness (i.e., aggressiveness) and the AR-A during PCa development and progression. And the analysis was performed in published and in-house RNA-seq datasets encompassing normal prostate, primary PCa (TCGA), metastatic castration-resistant PCa (mCRPC), PCa with long-term or neo-adjuvant androgen-deprivation therapy (ADT), and castration-resistant xenografts models. Results: In the normal prostate, significantly higher AR-A and lower stemness were observed in luminal cells compared to basal cells, consistent with the knowledge that luminal cells are differentiated cells regulated by AR signaling whereas the basal cell compartment harbors stem cell activity. In PCa, we have observed that: 1). Surprisingly, both stemness and AR-A are significantly increased in primary PCa compared to benign prostates; 2). In untreated primary PCa, tumor progression is accompanied by significantly reduced AR-A and an increasing trend of stemness; 3). In mCRPC, the AR-A inversely correlates with stemness; 4). Interestingly, while long-term ADT leads to reduced AR-A and increased stemness, short-term ADT during neo-adjuvant therapy (i.e., before the surgery) results in decreased stemness; 5). Our xenograft CRPC models have confirmed the AR-A is significantly reduced in CRPC. Conclusions: PCa development and early growth are accompanied by increased AR-A as well as the stemness. In contrast, the progression of treatment-naïve PCa is accompanied by decreasing AR-A and increasing stemness. In treatment-failed mCRPC, the AR-A shows an inverse correlation with the stemness. Duration of ADT influences the stemness, and stemness functions as a factor of treatment-induced reprogramming. Significance: Developing gene signature scores to assess stemness and AR signaling has allowed us to track the global differentiation status of PCa, and to better understand the cancer cell heterogeneity and plasticity along the course of PCa development, progression and treatment resistance. Our results suggest that increased stemness represents a ‘universal’ feature of PCa progression and aggressiveness and should be therapeutically targeted. Citation Format: Xiaozhuo Liu, Eduardo Cortes Gomez, Yibing Ji, Wanjun Song, Jun Yong, Jianmin Wang, Qiang Hu, Song Liu, Dean Tang. Bioinformatics approaches to dissecting androgen receptor activity and cancer stemness during prostate cancer development and progression [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 2703.