Andre Kajdacsy-Balla

Genetic alterations are closely associated with prostate cancer development and progression, but the RNA-derived transcriptional allele landscape of prostate cancer and cancer stem cells (CSCs) remains poorly understood. To characterize cancer-associated transcriptional alleles, we analyzed bulk and single-cell RNA sequencing (RNA-seq) data from primary human prostate cancer cells and their matched benign epithelial cells from non-cancerous regions of the same patients. Sequencing reads were aligned to the human reference genome (hg38) using STAR, and sequence variants were annotated with ANNOVAR. Most detected transcriptional alleles were located in noncoding regions, particularly within 3′ and 5′ untranslated regions, with single-nucleotide variants predominating and C>T substitutions occurring most frequently. Comparison of cancer and matched benign samples identified 223 genes carrying cancer-associated transcriptional alleles consistently detected across three independent patients. Seven of these genes showed differential expression between CSC and non-CSC populations, while 19 contained non-synonymous alleles, including 11 that are predicted to have potentially damaging effects. We identified ATF6 and KDM3A as candidate genes of potential functional interest. Single-cell RNA-seq analyses revealed differences in the number and distribution of detected transcriptional alleles between culture conditions, with 2D cancer cultures detecting more total, coding, and non-synonymous alleles than CSC-enriched 3D spheroids. CSC populations also exhibited fewer detected transcriptional alleles than non-CSC populations. Our findings provide a framework for characterizing transcriptional allele heterogeneity within the prostate cancer cellular hierarchy and identify candidate CSC-associated alterations for further investigation and functional validation. Finally, the cancer–benign matched strategy used in this study provides additional molecular evidence supporting the malignant origin of the tumor-derived cancer cells.

Cadmium (Cd) is a widespread environmental pollutant with several adverse effects on the general population. While Cd is a well-established risk factor for some cancers, such as lung cancer, its impact on prostate cancer (PCa) is not well understood. PCa mortality is associated with its progression to metastatic spread. This underscores the importance of studying the environmental/or molecular factors that govern the progression from organ-confined tumors to widely metastatic disease. To date, most studies addressing the effects of Cd on PCa are focused on the incidence rather than the progression/outcome. Furthermore, most of these epidemiological studies are limited by the small number of samples and the fact that most of these studies measured Cd levels in the air, blood, or urine, which is less applicable for addressing associations in environmental exposure than the measurement of Cd concentrations in the prostate microenvironment. It is still unknown whether Cd is a driver or a consequence of PCa aggressiveness. Addressing the plausibility of causality requires using proper in vitro and in vivo models for sub-micromolar Cd doses that mimic environmental exposure. Most in vitro studies addressing the functional and molecular effects of Cd are limited by the exclusive use of aggressive PCa cell models and very high micromolar unbound Cd concentrations, which are irrelevant for environmental exposure. Significantly, few studies have addressed the effects of sub-micromolar Cd concentrations. Hence, we suggest using nanomolar concentration that resembles real-life exposure, using less aggressive in vitro models such as RWPE-2, employing 3D organoid culture systems, and adopting high throughput-omics techniques, including metallomics, and using transgenic animal models might represent a more effective model. Here, we focus on reports on the impact of Cd on the progression and aggressiveness of already-established PCa instead of on the initial steps of carcinogenesis. We suggest potential future directions for substantiating the plausible link between Cd exposure and PCa aggressiveness.

Protein arginine methylation is among the most important post-translational modifications and has been studied in cancers such as those of the lung and breast. However, comparatively less has been investigated regarding hepatocellular carcinoma, with an annual incidence of almost one million cases. Through using in silico methods, this study examined arginine methylation-related gene expression and methylation levels, and alongside network and enrichment analysis attempted to find how said genes can drive tumorigenesis and offer possible therapeutic targets. We found a robust relationship among the selected methylation genes, with ⅞ showing prognostic value regarding overall survival, and a medley of non-arginine methylation pathways also being highlighted through the aforementioned analysis. This study furthers our knowledge of the methylation and expression patterns of arginine histone methylation-related genes, offering jumping points for further wet-lab studies.

The escalating prevalence of bladder cancer, particularly urothelial carcinoma, necessitates innovative approaches for prognosis and therapy. This study delves into the significance of genes related to epithelial–mesenchymal transition (EMT), a process inherently linked to carcinogenesis and comparatively better studied in other cancers. We examined 1184 EMT-related gene expression levels in bladder urothelial cancer cases through the TCGA dataset. Genes shown to be differentially expressed in relation to survival underwent further network and enrichment analysis to uncover how they might shape disease outcomes. Our in silico analysis revealed a subset of 32 genes, including those significantly represented in biological pathways such as VEGF signaling and bacterium response. In addition, these genes interact with genes involved in the JAK-STAT signaling pathway. Additionally, some of those 32 genes have been linked to immunomodulators such as chemokines CCL15 and CCL18, as well as to various immune cell infiltrates. Our findings highlight the prognostic utility of various EMT-related genes and identify possible modulators of their effect on survival, allowing for further targeted wet lab research and possible therapeutic intervention.

It is crucial to understand molecular alterations in breast cancer and how they relate to clinicopathologic factors. We have previously shown that the glucocorticoid receptor (GCR) protein expression was reduced in invasive breast carcinoma compared to normal breast tissue. Glucocorticoids, signaling through the GCR, regulate several cellular processes via downstream targets such as serum/glucocorticoid-regulated kinase 1 (SGK1) and B-cell lymphoma 2 (Bcl-2). We measured the expression of SGK1 and Bcl-2, in respective breast cancer tissue arrays, from a multiracial cohort of breast cancer patients. Higher cytoplasmic SGK1 staining was stronger in breast cancer tissue compared to normal tissue, especially in hormone receptor-negative cases. Conversely, the expression of cytoplasmic Bcl-2 was reduced in breast cancer compared to normal tissue, especially in hormone receptor-negative cases. Bcl-2 staining was associated with the self-reported racial/ethnic category, an earlier clinical stage, a lower histological grade, and a higher survival rate. Bcl-2 expression was associated with longer survival in models adjusted for age and race (HR = 0.32, 95% CI: 0.15, 0.65), and Bcl-2 expression remained strongly positively associated with protection from breast cancer death, with additional adjustments for ER/PR status (HR = 0.41, 95% CI: 0.2, 0.85). SGK1 and Bcl-2 may play biological roles in breast cancer development and/or progression.