ABSTRACT
Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Molecular analyses of human and murine samples define microenvironmental consequences of obesity that foster tumorigenesis rather than new driver gene mutations, including significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in response to obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment and implicate endocrine-exocrine signaling beyond insulin in PDAC development.
Subject(s)
Carcinoma, Pancreatic Ductal/etiology , Carcinoma, Pancreatic Ductal/metabolism , Obesity/metabolism , Animals , Carcinogenesis/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Line , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Disease Models, Animal , Disease Progression , Endocrine Cells/metabolism , Exocrine Glands/metabolism , Female , Gene Expression Regulation, Neoplastic/genetics , Humans , Male , Mice , Mice, Inbred C57BL , Mutation/genetics , Obesity/genetics , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Signal Transduction/genetics , Tumor Microenvironment/physiology , Pancreatic NeoplasmsABSTRACT
The new pentadentate 3d9 complex [CuII(LN2Py3)](PF6)2 (1) based on a nitrogen-rich framework acts as an electrocatalyst toward dihydrogen production from water. This species is active at pHs 7 and 2.5 yielding respective TON3h values of 1670 and 3900. Comparison of the molecular structure of 1 with that of the reduced [CuI(LN2Py3)]PF6 (2) evidences elongated Cu-N bond lengths resulting from an increased electron density around the 3d10 CuI center. The absence of nanoparticulate formation indicates that molecular mechanisms prevail at both pHs. Furthermore, experimental and DFT data support that distinct mechanisms are operative: while the metal center plays a key role at pH 7, one dangling pyridine moiety gets protonated at pH 2.5 and becomes actively involved in a relay mechanism. In both cases the CuIII-H- intermediate seems to be bypassed by PCET processes.
