Personalized 3D models for prostate cancer surgery
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LKB1 inactivation promotes epigenetic remodeling-induced lineage plasticity and antiandrogen resistance in prostate cancer
Epigenetic regulation profoundly influences the fate of cancer cells and their capacity to switch between lineages by modulating essential gene expression, thereby shaping tumor heterogeneity and therapy response. In castration-resistant prostate cancer (CRPC), the intricacies behind androgen receptor (AR)-independent lineage plasticity remain unclear, leading to a scarcity of effective clinical treatments. Utilizing single-cell RNA sequencing on both human and mouse prostate cancer samples, combined with whole-genome bisulfite sequencing and multiple genetically engineered mouse models, we investigated the molecular mechanism of AR-independent lineage plasticity and uncovered a potential therapeutic strategy. Single-cell transcriptomic profiling of human prostate cancers, both pre- and post-androgen deprivation therapy, revealed an association between liver kinase B1 (LKB1) pathway inactivation and AR independence. LKB1 inactivation led to AR-independent lineage plasticity and global DNA hypomethylation during prostate cancer progression. Importantly, the pharmacological inhibition of TET enzymes and supplementation with S-adenosyl methionine were found to effectively suppress AR-independent prostate cancer growth. These insights shed light on the mechanism driving AR-independent lineage plasticity and propose a potential therapeutic strategy by targeting DNA hypomethylation in AR-independent CRPC.
SREBF1-based metabolic reprogramming in prostate cancer promotes tumor ferroptosis resistance
Metabolic reprogramming in prostate cancer has been widely recognized as a promoter of tumor progression and treatment resistance. This study investigated its association with ferroptosis resistance in prostate cancer and explored its therapeutic potential. In this study, we identified differences in the epithelial characteristics between normal prostate tissue and tissues of various types of prostate cancer using single-cell sequencing. Through transcription factor regulatory network analysis, we focused on the candidate transcription factor, SREBF1. We identified the differences in SREBF1 transcriptional activity and its association with ferroptosis, and further verified this association using hdWGCNA. We constructed a risk score based on SREBF1 target genes associated with the biochemical recurrence of prostate cancer by combining bulk RNA analysis. Finally, we verified the effects of the SREBPs inhibitor Betulin on the treatment of prostate cancer and its chemosensitization effect. We observed characteristic differences in fatty acid and cholesterol metabolism between normal prostate tissue and prostate cancer tissue, identifying high transcriptional activity of SREBF1 in prostate cancer tissue. This indicates that SREBF1 is crucial for the metabolic reprogramming of prostate cancer, and that its mediated metabolic changes promoted ferroptosis resistance in prostate cancer in multiple ways. SREBF1 target genes are associated with biochemical recurrence of prostate cancer. Finally, our experiments verified that SREBF1 inhibitors can significantly promote an increase in ROS, the decrease in GSH, and the decrease in mitochondrial membrane potential in prostate cancer cells and confirmed their chemosensitization effect in vivo. Our findings highlighted a close association between SREBF1 and ferroptosis resistance in prostate cancer. SREBF1 significantly influences metabolic reprogramming in prostate cancer cells, leading to ferroptosis resistance. Importantly, our results demonstrated that SREBF1 inhibitors can significantly enhance the therapeutic effect and chemosensitization of prostate cancer, suggesting a promising therapeutic potential for the treatment of prostate cancer.
Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation
Compared to most tumors that are more glycolytic, primary prostate cancer is less glycolytic but more dependent on TCA cycle coupled with OXPHOS for its energy demand. This unique metabolic energetic feature is attributed to activation of mitochondrial m-aconitase in TCA caused by decreased cellular Zn level. Evidence suggests that a small subpopulation of cancer cells within prostate tumors, designated as prostate cancer stem cells (PCSCs), play significant roles in advanced prostate cancer progression. However, their cellular energetics status is still poorly understood. Nuclear receptor ERRα (ESRRA) is a key regulator of energy metabolism. Previous studies characterize that ERRα exhibits an upregulation in prostate cancer and can perform multiple oncogenic functions. Here, we demonstrate a novel role of ERRα in the control of stemness and energetics metabolism in PCSCs via a mechanism of combined transrepression of Zn transporter ZIP1 in reducing intracellular Zn uptake and transactivation of ACO2 (m-aconitase) in completion of TCA cycle. Results also showed that restoration of Zn accumulation by treatment with a Zn ionophore Clioquinol could significantly suppress both in vitro growth of PCSCs and also their in vivo tumorigenicity, implicating that enhanced cellular Zn uptake could be a potential therapeutic approach for targeting PCSCs in advanced prostate cancer.
Algorithmic personalization: a study of knowledge gaps and digital media literacy
Understanding personalized content and its societal implications is critical in the digital media era. This article introduces a novel information-analytical system designed to evaluate the level of knowledge among different social classes regarding personalized content in the digital media ecosystem. Utilizing data from 1213 Czech respondents, we employ fuzzy logic and multidimensional membership functions for an in-depth evaluation of the populace’s awareness. It categorizes population knowledge on personalization processes, their preferences, and trust levels and advocates control mechanisms over online content. The research reveals significant insights into demographic disparities in digital media literacy, emphasizing the urgent need for targeted educational programs. This paper presents a pioneering methodological framework and lays the groundwork for future investigations into personalized media services’ ethical considerations and socio-political dynamics. Our study contributes to the broader discourse on media literacy, algorithmic understanding, and protecting informational self-determination in the digital age.
EphB4-ephrin-B2 are targets in castration resistant prostate cancer
PI3K pathway activation is a common and early event in prostate cancer, from loss of function mutations in PTEN, or activating mutations in PIK3Ca or AKT leading to constitutive activation, induction of growth factor-receptors kinase EphB4 and its ligand ephrin-B2. We hypothesized that induction of EphB4 is an early event required for tumor initiation. Secondly, we hypothesized that EphB4 remains relevant when prostate cancer becomes androgen independent.
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