Metabolic Regulation of Cell Identity and Therapy Response in Prostate Cancer

Prostate cancer growth is driven by androgen signaling using the androgen receptor (AR). Androgen deprivation therapy (ADT) is the gold standard for prostate cancer, but the majority of ADT-treated patients develop resistance, which often involves the loss of luminal lineage identity and AR-independent growth. Previous work has shown that modulating metabolism can regulate cell fate in many tissues. Therefore, it is important to understand the mechanisms behind how altered metabolism affects lineage identity and response to AR blockade, a common form of treatment for prostate cancer involving blocking AR signaling. Inhibition of mitochondrial pyruvate carrier 1, an essential metabolic enzyme, with small molecule UK5099 in mouse basalderived nonmalignant organoids blocked luminal differentiation and UK5099-treated organoids retained a basal phenotype. AR expression decreased substantially in vehicle-treated organoids, but had a more modest decrease in UK5099-treated organoids in castrated conditions. Expression of Tmprss2, an AR target gene, slightly decreased in vehicle-treated organoids, yet slightly increased with UK5099 treatment in castrated conditions. The organoid size assay was a useful tool in determining how modulating metabolism affected the impact of castration on organoid diameter in 3D ex vivo organoid culture. It shows that the number of days post-castration onset could affect the relative size of different treatment groups, but 6 days after castration vehicletreated organoids were smaller in castrated conditions than control conditions. Castrated UK5099-treated organoids, however, appeared slightly larger than the UK5099 control. An investigation into differentiation and metabolic pathways affected by UK5099-treatment revealed differential expression of phosphorylated p-65 (NFkB), changes in β-catenin nuclear translocation, and increased citrate synthase, OGDH, and MDH2 in the nucleus. This shows that UK5099 affects both differentiation and metabolism. Collectively, these results show that altering metabolism affects lineage identity and response to AR blockade. Modulation of metabolism appears to be a potential method of improving clinical outcomes for advanced prostate cancer

Prenatal exposure to ambient air pollutants and congenital heart defects: An umbrella review

Background: Prenatal exposure to ambient air pollutants has been linked to congenital heart defects (CHD), but findings of existing systematic reviews have been mixed. Objective: To assess the epidemiological evidence on associations between prenatal exposure to ambient air pollutants and CHD subtypes, based on a systematic overview of reviews (“umbrella review”). Methods: We conducted a systematic search for reviews assessing associations between prenatal exposure to criteria air pollutants and CHD. The risk of bias was evaluated using the Risk of Bias in Systematic Reviews (ROBIS) tool. The certainty of the systematic review findings was graded using the Navigation Guide methodology. Results: We identified eleven systematic reviews, including eight with meta-analyses, assessing in total 35 primary studies of prenatal exposure to criteria air pollutants and various CHD subtypes. The certainty of the findings of four meta-analyses indicating an increased risk for coarctation of the aorta associated with nitrogen dioxide exposure was rated as moderate. The certainty of findings indicating positive, inverse, or null associations for other pollutant-subtype combinations was rated as very low to low, based on low precision and high statistical heterogeneity of summary odds ratios (SOR), substantial inconsistencies between review findings, and methodological limitations of the systematic reviews. Discussion: The inconsistent findings and high statistical heterogeneity of many SOR of the included systematic reviews may partly be traced to differences in methodological approaches, and the risk of bias across included reviews (e.g., inclusion criteria, systematic search strategies, synthesis methods) and primary studies (e.g., exposure assessment, diagnostic criteria). Adherence to appropriate systematic review guidelines for environmental health research, as well as rigorous evaluation of risk of bias in primary studies, are essential for future risk assessments and policy-making. Still, our findings suggest that prenatal exposure to ambient air pollutants may increase risks for at least some CHD subtypes

Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment

Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity