Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with few effective treatments. Here we show that the mitochondrial calcium uniporter (MCU) promotes PDAC cell migration, invasion, metastasis, and metabolic stress resistance by activating the Keap1-Nrf2 antioxidant program. The cystine transporter SLC7A11 was identified as a druggable target downstream of the MCU-Nrf2 axis. Paradoxically, despite the increased ability to uptake cystine, MCU-overexpressing PDAC demonstrated characteristics typical of cystine-deprived cells and were hypersensitive to cystine deprivation-induced ferroptosis. Pharmacologic inhibitors of SLC7A11 effectively induced tumor regression and abrogated MCU-driven metastasis in PDAC. In patient-derived organoid models in vitro and patient-derived xenograft models in vivo, MCU-high PDAC demonstrated increased sensitivity to SLC7A11 inhibition compared with MCU-low tumors. These data suggest that MCU is able to promote resistance to metabolic stress and to drive PDAC metastasis in a cystine-dependent manner. MCU-mediated cystine addiction could be exploited as a therapeutic vulnerability to inhibit PDAC tumor growth and to prevent metastasis. Significance: Elevated mitochondrial calcium uptake in PDAC promotes metastasis but exposes cystine addiction and ferroptosis sensitivity that could be targeted to improve pancreatic cancer treatment.

Ergothioneine (ERGO) is a potent antioxidant and anti-inflammatory amino acid that is produced in nature mainly by non-yeast fungi, cyanobacteria, and mycobacteria. Mounting evidence suggests that ERGO can be considered a longevity vitamin that can mitigate chronic diseases of aging and thereby increase life expectancy. Humans must obtain ERGO from their diet, and it is therefore important to know which foods contain it. Although ERGO is not produced by plants it is found in plant products such as grain, apparently because detrital or symbiotic soil fungi pass on ERGO to plants through their roots. Besides differences between plant species in their ability to accumulate ERGO, how they are managed might also affect its concentration. Soil tillage has been shown to reduce soil fungal biomass, and therefore ERGO contents in maize, soybeans, and oats grown in soil managed with annual moldboard plowing (most intensive), chisel/disking (less intensive), or no-tillage (least intensive) in crop rotation were compared. ERGO concentrations declined in all three crops as tillage intensity increased, with reductions from no till to moldboard plow of approximately 30% in all three crops. Because crop yield was also negatively impacted by intensive tillage, ERGO yield per hectare was reduced even more due to increasing tillage intensity. This study is one of the first to show that soil health improving practices that minimize soil disturbance can directly enhance a key dietary factor associated with long-term human health.

Societal Impact Statement: Evidence has emerged that the antioxidant ergothioneine may be important in preventing many inflammatory diseases in humans. However, ergothioneine is not produced by humans or plants and is only made by fungi and some bacteria in soils. As such, humans get ergothioneine from eating fungi (mushrooms) or plants that take it up from the soil. In this study, we found that growing plants with beneficial fungi called arbuscular mycorrhizal fungi increased the amount of ergothioneine in plant tissues. This suggests that promoting agricultural practices that maintain healthy populations of beneficial soil fungi may improve the nutritional quality of crops.Summary: The amino acid ergothioneine (ERGO) has recently gained attention as an antioxidant that benefits human health. ERGO is produced by fungi and mycobacteria in soils and is acquired only from diet. The mechanism by which ERGO is transferred from soil to plant is unknown. Recent work has shown that tillage reduces the amount of ERGO in crops. As tillage also reduces arbuscular mycorrhizal fungi (AMF) populations, we examined the relationship between AMF and plant ERGO uptake. We grew asparagus, black beans, wheat, and oats with a variety of single and mixed species AMF inocula and compared ERGO levels of these plants to plants that were uninoculated. Mycorrhizal inoculation enhanced ERGO content across all plants. There was a positive correlation between AMF colonization level and plant ERGO content. AMF appear to be important mediators of plant ERGO uptake. Future research is needed to identify the mechanism that leads to higher ERGO in plants colonized by AMF in order to promote farming practices that enhance AMF populations and increase crop ERGO concentration in field settings.

Aim: 8-iso-prostaglandin F2α is a biomarker of lipid peroxidation, and one of the most commonly used measures of oxidative stress. It is an established biomarker of lung cancer risk. It is commonly measured by enzyme-linked immunosorbent assay. Given its importance, we developed a stable isotope dilution UPLC-tandem mass spectrometric method for the rapid determination of 8-isoprostane in blood. Methods: We tested the discriminatory capability of the method in 49 lung cancer patients, 55 benign lung nodule patients detected by chest X-ray, and 41 patients with chronic obstructive pulmonary disease (COPD) or asthma. Results: Significant differences were found in mean 8-isoprostane levels between the three groups (p = 0.027), and post-hoc tests found higher levels in the lung cancer patients than in patients with benign nodules (p = 0.032) and COPD/asthma (p = 0.014). The receiving operating characteristic area under the curve (AUC) was 0.69 for differentiating the lung cancer group from the benign nodule group, and 0.7 for differentiating from the COPD/asthma group. Conclusions: The UPLC-MS/MS-based method is an efficient analytical tool for measuring 8-isoprostane plasma concentrations. The results suggest exploring its utility as a marker for early lung cancer screening.

BACKGROUND: Lung cancer is the leading cause of cancer mortality worldwide. The collection of exhaled breath condensate (EBC) is a non-invasive method that may have enormous potential as a biomarker for the early detection of lung cancer. OBJECTIVE: To investigate the proteomic differences of EBC between lung cancer and CT-detected benign nodule patients, and determine whether these proteins could be potential biomarkers. METHODS: Proteomic analysis was performed on individual samples from 10 lung cancer patients and 10 CT-detected benign nodule patients using data-independent acquisition (DIA) mass spectrometry. RESULTS: A total of 1,254 proteins were identified, and 21 proteins were differentially expressed in the lung adenocarcinoma group compared to the benign nodule group (p< 0.05). The GO analysis showed that most of these proteins were involved in neutrophil-related biological processes, and the KEGG analysis showed these proteins were mostly annotated to pyruvate and propanoate metabolism. Through protein-protein interactions (PPIs) analysis, ME1 and LDHB contributed most to the interaction-network of these proteins. CONCLUSION: Significantly differentially expressed proteins were detected between lung cancer and the CT-detected benign nodule group from EBC samples, and these proteins might serve as potential novel biomarkers of EBC for early lung cancer detection.