Evans, Ronald M

Pancreatic β cells secrete insulin in response to glucose, a process that is regulated at multiple levels, including a network of input signals from other organ systems. Impaired islet function contributes to the pathogenesis of type 2 diabetes mellitus (T2DM), and targeting inter‐organ communications, such as GLP‐1 signalling, to enhance β‐cell function has been proven to be a successful therapeutic strategy in the last decade. In this review, we will discuss recent advances in inter‐organ communication from the metabolic, immune and neural system to pancreatic islets, their biological implication in normal pancreas endocrine function and their role in the (mal)adaptive responses of islet to nutrition‐induced stress.

Significance Macrophages regulate many aspects of the innate immune response and the activation of adaptive immunity following exposure to microbial ligands. However, macrophages can also contribute to inflammation underlying diseases such as atherosclerosis and obesity. Epigenetic regulators control inflammatory gene regulation and, as such, are potential targets for modulation of the inflammatory response. Here, we show that inhibitors and degraders of the bromodomain protein BRD9, a subunit of the noncanonical BAF complex, limit inflammation by specifically blocking the induction of interferon-stimulated genes. This effect overlaps with the transcriptional responses with the BET inhibitor JQ1 but affects fewer genes and is more specific in scope. Our results suggest that BRD9 inhibitors/degraders may be therapeutically relevant agents to limit interferon-associated inflammation.

Significance Glucocorticoids are widely prescribed antiinflammatory drugs that suppress inflammatory gene expression through activation of the glucocorticoid receptor (GR); however, the mechanisms of GR-mediated repression are not fully understood. We show here that bromodomain containing 9 (BRD9), a component of the SWI/SNF chromatin remodeling complex, modulates GR activity in bone marrow-derived macrophages. Loss of BRD9 activity in macrophages attenuated the response to liposaccharides and interferon inflammatory stimuli. Notably, BRD9 inhibition synergized with the synthetic glucocorticoid dexamethasone to suppress the inflammatory response in macrophages. Our data support a model in which BRD9 restricts GR binding at a subset of inflammatory related genes, and suggests that BRD9 inhibitors may increase the efficacy of glucocorticoids.

Abstract Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in TP53 (87%) and KRAS (73%), amplification of MYC (47%), and homozygous deletion of CDKN2A (40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase SMYD2 and the pancreatic cancer stem cell regulator RORC in all three ASCPs, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the FGFR1-ERLIN2 fusion–positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer. Significance: These data provide a unique description of the ASCP genomic and epigenomic landscape and identify candidate therapeutic targets for this dismal cancer.

Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear hormone receptor that is mainly involved in lipid metabolism. Recent studies have suggested that PPAR-δ agonists exert vascular protective effects. The present study was designed to characterize vascular function in mice with genetic inactivation of PPAR-δ in the endothelium. Mice with vascular endothelial cell-specific deletion of the PPAR-δ gene (ePPARδ−/− mice) were generated using loxP/Cre technology. ePPARδ−/− mice were normotensive and did not display any sign of metabolic syndrome. Endothelium-dependent relaxations to ACh and endothelium-independent relaxations to the nitric oxide (NO) donor diethylammonium ( Z)-1-( N, N-diethylamino)diazen-1-ium-1,2-diolate were both significantly impaired in the aorta and carotid arteries of ePPARδ−/− mice ( P < 0.05). In ePPARδ−/− mouse aortas, phosphorylation of endothelial NO synthase at Ser1177 was significantly decreased ( P < 0.05). However, basal levels of cGMP were unexpectedly increased ( P < 0.05). Enzymatic activity of GTP-cyclohydrolase I and tetrahydrobiopterin levels were also enhanced in ePPARδ−/− mice ( P < 0.05). Most notably, endothelium-specific deletion of the PPAR-δ gene significantly decreased protein expressions of catalase and glutathione peroxidase 1 and resulted in increased levels of H2O2 in the aorta ( P < 0.05). In contrast, superoxide anion production was unaltered. Moreover, treatment with catalase prevented the endothelial dysfunction and elevation of cGMP detected in aortas of ePPARδ−/− mice. The findings suggest that increased levels of cGMP caused by H2O2 impair vasodilator reactivity to endogenous and exogenous NO. We speculate that chronic elevation of H2O2 predisposes PPAR-δ-deficient arteries to oxidative stress and vascular dysfunction.