Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

Background: Pancreatic cancer cells exhibit up-regulated glycolysis (the “Warburg effect”).Results: Reversing the Warburg phenotype protects pancreatic cancer cells from glycolytic inhibitor-induced ATP depletion, plasma membrane calcium pump (PMCA) inhibition, and [Ca2+]i overload.Conclusion: Glycolytic ATP is critical for PMCA function in pancreatic cancer.Significance: The glycolytic dependence of the PMCA may represent a novel therapeutic target in pancreatic cancer.

Background: Impaired metabolism and cytosolic Ca 2ϩ overload in pancreatic acinar cells can trigger pancreatitis. Results: Insulin protected cells from oxidant-induced Ca 2ϩ overload, inhibition of the plasma membrane calcium pump (PMCA), and ATP depletion. Conclusion: Insulin switches metabolism toward glycolysis and fuels the PMCA even when mitochondria are impaired. Significance: This mechanism may provide an important therapeutic strategy for pancreatitis.

Ion channels can regulate the plasma membrane potential (Vm) and cell migration as a result of altered ion flux. However, the mechanism by which Vm regulates motility remains unclear. Here, we show that the Nav1.5 sodium channel carries persistent inward Na+ current which depolarizes the resting Vm at the timescale of minutes. This Nav1.5‐dependent Vm depolarization increases Rac1 colocalization with phosphatidylserine, to which it is anchored at the leading edge of migrating cells, promoting Rac1 activation. A genetically encoded FRET biosensor of Rac1 activation shows that depolarization‐induced Rac1 activation results in acquisition of a motile phenotype. By identifying Nav1.5‐mediated Vm depolarization as a regulator of Rac1 activation, we link ionic and electrical signaling at the plasma membrane to small GTPase‐dependent cytoskeletal reorganization and cellular migration. We uncover a novel and unexpected mechanism for Rac1 activation, which fine tunes cell migration in response to ionic and/or electric field changes in the local microenvironment.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has poor survival and treatment options. PDAC cells shift their metabolism towards glycolysis, which fuels the plasma membrane calcium pump (PMCA), thereby preventing Ca 2+-dependent cell death. The ATP-generating pyruvate kinase-M2 (PKM2) is oncogenic and overexpressed in PDAC. This study investigated the PKM2derived ATP supply to the PMCA as a potential therapeutic locus. METHODS: PDAC cell growth, migration and death were assessed by using sulforhodamine-B/tetrazolium-based assays, gap closure assay and poly-ADP ribose polymerase (PARP1) cleavage, respectively. Cellular ATP and metabolism were assessed using luciferase/fluorescent-based assays and the Seahorse XFe96 analyzer, respectively. Cell surface biotinylation identified membraneassociated proteins. Fura-2 imaging was used to assess cytosolic Ca 2+ overload and in situ Ca 2+ clearance. PKM2 knockdown was achieved using siRNA. RESULTS: The PKM2 inhibitor (shikonin) reduced PDAC cell proliferation, cell migration and induced cell death. This was due to inhibition of glycolysis, ATP depletion, inhibition of PMCA and cytotoxic Ca 2+ overload. PKM2 associates with plasma membrane proteins providing a privileged ATP supply to the PMCA. PKM2 knockdown reduced PMCA activity and reduced the sensitivity of shikonin-induced cell death. CONCLUSIONS: Cutting off the PKM2-derived ATP supply to the PMCA represents a novel therapeutic strategy for the treatment of PDAC.