👤 Dianna J Magliano

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with KRAS mutations in ~ 95% of cases. While KRAS inhibitors have shown promise, therapeutic resistance necessitates combination approaches. In particular, it is important to understand how downstream signaling of KRAS supports PDAC growth. For example, DUSP6 has emerged as an important dual-specificity phosphatase regulating KRAS-MAPK signaling. DUSP6 is markedly overexpressed in PDAC tumors compared to normal pancreatic tissue, with transcriptomic and single-cell RNA-seq analyses revealing its enrichment in epithelial tumor cells, especially in metastatic lesions. High DUSP6 expression correlates with the quasi-mesenchymal/squamous molecular subtype and poorer survival outcomes. Gene set enrichment analyses linked DUSP6 to pathways involved in cell migration and metabolism in metastatic samples. Functionally, DUSP6 knockdown in PDAC cells increases ERK/MAPK activation and alters migration. Metabolic profiling revealed enhanced basal glycolysis upon DUSP6 suppression. However, combined glycolysis inhibition and DUSP6 knockdown did not affect migration, suggesting that glycolytic changes are not the driver of altered migratory behavior. These findings reveal that DUSP6 independently regulates migration and metabolism in PDAC, emphasizing its dual role in disease progression. This study underscores the significance of DUSP6 as a potential therapeutic target and provides new insights into its contributions to PDAC progression. Show less

Obesity and related metabolic diseases show clear sex-related differences. The growing burden of these diseases calls for better understanding of the age- and sex-related metabolic consequences. High-throughput lipidomic analyses of population-based cohorts offer an opportunity to identify disease-risk-associated biomarkers and to improve our understanding of lipid metabolism and biology at a population level. Here, we comprehensively examined the relationship between lipid classes/subclasses and molecular species with age, sex, and body mass index (BMI). Furthermore, we evaluated sex specificity in the association of the plasma lipidome with age and BMI. Some 747 targeted lipid measures, representing 706 molecular lipid species across 36 classes/subclasses, were measured using a high-performance liquid chromatography coupled mass spectrometer on a total of 10,339 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), with 563 lipid species being validated externally on 4,207 participants of the Busselton Health Study (BHS). Heat maps were constructed to visualise the relative differences in lipidomic profile between men and women. Multivariable linear regression analyses, including sex-interaction terms, were performed to assess the associations of lipid species with cardiometabolic phenotypes. Associations with age and sex were found for 472 (66.9%) and 583 (82.6%) lipid species, respectively. We further demonstrated that age-associated lipidomic fingerprints differed by sex. Specific classes of ether-phospholipids and lysophospholipids (calculated as the sum composition of the species within the class) were inversely associated with age in men only. In analyses with women alone, higher triacylglycerol and lower lysoalkylphosphatidylcholine species were observed among postmenopausal women compared with premenopausal women. We also identified sex-specific associations of lipid species with obesity. Lysophospholipids were negatively associated with BMI in both sexes (with a larger effect size in men), whilst acylcarnitine species showed opposing associations based on sex (positive association in women and negative association in men). Finally, by utilising specific lipid ratios as a proxy for enzymatic activity, we identified stearoyl CoA desaturase (SCD-1), fatty acid desaturase 3 (FADS3), and plasmanylethanolamine Δ1-desaturase activities, as well as the sphingolipid metabolic pathway, as constituent perturbations of cardiometabolic phenotypes. Our analyses elucidate the effect of age and sex on lipid metabolism by offering a comprehensive view of the lipidomic profiles associated with common cardiometabolic risk factors. These findings have implications for age- and sex-dependent lipid metabolism in health and disease and suggest the need for sex stratification during lipid biomarker discovery, establishing biological reference intervals for assessment of disease risk. Show less