Pancreatic Cell News Volume 10.33 | Aug 27 2019

TOP STORY

The Histone Demethylase KDM3A, Increased in Human Pancreatic Tumors, Regulates Expression of DCLK1 In and Promotes Tumorigenesis in Mice

Scientists knocked down lysine demethylase 3A (KDM3A) in MiaPaCa-2 and S2-007 pancreatic cancer cell lines and overexpressed KDM3A in HPNE cells; they evaluated cell migration, invasion, and spheroid formation under hypoxic and normoxic conditions. Nude mice were given orthotopic injections of S2-007 cells, with or without knockdown of KDM3A, and HPNE cells, with or without overexpression of KDM3A; tumor growth was assessed. [Gastroenterology] Abstract

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DIABETES & PANCREATITIS

Allosteric Modulation of β-Cell M₃ Muscarinic Acetylcholine Receptors Greatly Improves Glucose Homeostasis in Lean and Obese Mice

Investigators demonstrated that VU0119498, a drug known to act as a positive allosteric modulator (PAM) at M3 muscarinic acetylcholine (ACh) receptors (M3Rs), significantly augmented ACh-induced insulin release from cultured β cells and mouse and human pancreatic islets. This stimulatory effect was absent in islets prepared from mice lacking M3Rs, indicative of the involvement of M3Rs. [Proc Natl Acad Sci USA] Abstract

Agonist-Induced Membrane Nanodomain Clustering Drives GLP-1 Receptor Responses in Pancreatic Beta Cells

Researchers demonstrated an important role for the translocation of active glucagon-like peptide-1 receptor (GLP-1R) into liquid-ordered plasma membrane nanodomains, which acted as hotspots for optimal coordination of intracellular signaling and clathrin-mediated endocytosis. This process was dynamically regulated by agonist binding through palmitoylation of the GLP-1R at its carboxyl-terminal tail. [PLoS Biol] Full Article

The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function

Early embryonic deletion of just the Swi/Snf Brg1 ATPase subunit reduced multipotent pancreatic progenitor cell proliferation and resulted in pancreas hypoplasia. In contrast, removal of both Swi/Snf ATPase subunits, Brg1 and Brm, was necessary to compromise adult islet β-cell activity, which included whole-animal glucose intolerance, hyperglycemia, and impaired insulin secretion. [Diabetes] Full Article

Hydrogel Platform for In Vitro Three Dimensional Assembly of Human Stem Cell-Derived Islet Cells and Endothelial Cells

Investigators developed a strategy of assembling human embryonic stem cell-derived islet cells with endothelial cells into three-dimensional aggregates on a hydrogel. The resulting islet organoids expressed β cell and other endocrine markers and were functional, capable of undergoing glucose-stimulated insulin secretion. [Acta Biomater] Abstract | Graphical Abstract

Sitagliptin Favorably Modulates Immune-Relevant Pathways in Human Beta Cells

Scientists studied the effects of three antidiabetic drugs on immune-relevant pathways in a human beta cell line. Costimulatory molecule expression, cytokine secretion, and gene expression profiles were evaluated at different time points following challenge with the aforementioned antidiabetic agents. [Pharmacol Res] Abstract | Graphical Abstract

Islets from Human Donors with Higher but Not Lower Hemoglobin A1c Levels Respond to Gastrin Treatment In Vitro

Treatment of isolated human islets with gastrin I for 48 hours resulted in increased expression of insulin, glucagon and somatostatin transcripts. These increases were significantly correlated with the levels of donor hemoglobin A1_c (HbA1_c) but not BMI or age. In addition, gastrin treatment resulted in increased expression of PDX1, NKX6.1, NKX2.2, MNX1 and HHEX in islets from donors with HbA1_c greater than 42 mmol/mol. [PLoS One] Full Article

Regulation of cAMP Accumulation and Activity by Distinct Phosphodiesterase Subtypes in INS-1 Cells and Human Pancreatic β-Cells

Using a genetically encoded, FRET-based cAMP sensor, the authors found that the phosphodiesterase (PDE)1 inhibitor 8MM-IBMX, elevated cAMP levels in the absence of glucose to a greater extent than either the PDE3 inhibitor cilostamide or the PDE4 inhibitor rolipram. In 18 mM glucose, PDE1 inhibition elevated cAMP levels to a greater extent than PDE3 inhibition in INS-1 cells, while PDE4 inhibition was without effect. [PLoS One] Full Article

PANCREATIC CANCER

A Yap-Myc-Sox2-p53 Regulatory Network Dictates Metabolic Homeostasis and Differentiation in Kras-Driven Pancreatic Ductal Adenocarcinomas

Integrated transcriptional and metabolomics analysis revealed that Yap transcribed Myc and cooperated with Myc to maintain global transcription of metabolic genes. Yap loss triggered acute metabolic stress, which caused tumor regression while inducing epigenetic reprogramming and Sox2 upregulation in a subset of pancreatic neoplastic cells. [Dev Cell] Full Article | Press Release | Graphical Abstract

Immunoevolution of Mouse Pancreatic Organoid Isografts from Preinvasive to Metastatic Disease

Researchers tracked the immunoevolution of pancreatic ductal adenocarcinoma (PDA) in a genetically-defined transplantable model of mouse pancreatic tumor organoids that recapitulated the progression of the disease from early preinvasive lesions to metastatic carcinomas. They demonstrated that organoid-derived isografts could be used as a biological source of biomarkers of aggressive molecular subtypes of human PDA. [Sci Rep] Full Article

Inclusion Complexes of Melphalan with Gemini-Conjugated β-Cyclodextrin: Physicochemical Properties and Chemotherapeutic Efficacy in In-Vitro Tumor Models

In vitro evaluations were performed using monolayer, 3D spheroid, and melphalan (Mel)-resistant melanoma cell lines. The 18:1βCDg-Mel complex showed significant enhancement in the chemotherapeutic efficacy of Mel with 2-3-fold decrease in Mel half maximal inhibitory concentration values. [Pharmaceutics] Full Article

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Understanding the Glucoregulatory Mechanisms of Metformin in Type 2 Diabetes Mellitus

Despite its position as the first-line drug for treatment of type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level-lowering effects of metformin still remain incompletely understood. Emerging evidence suggests that metformin could improve obesity-induced meta-inflammation via direct and indirect effects on tissue-resident immune cells in metabolic organs. [Nat Rev Endocrinol] Abstract

New Insights into Beta Cell GLP-1 Receptor and cAMP Signaling

The authors discuss recent advances in the current research on the GLP-1/GLP-1R system in beta cells, including the regulation of signaling by endocytic trafficking as well as the application of concepts such as signal bias, allosteric modulation, dual agonism, polymorphic receptor variants, spatial compartmentalization of cAMP signaling and new downstream signaling targets involved in the control of beta cell function. [J Mol Biol] Abstract | Graphical Abstract

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Enrollment in the Independent Investigator-Sponsored Phase III Metastatic Pancreatic Study ACELARATE Has Been Suspended Following a Prespecified Futility Analysis

NuCana plc reported that it has been informed by the Clatterbridge Cancer Center, the sponsor of the ongoing Phase III ACELARATE study, that the enrollment of new patients has been suspended on the advice of the Independent Safety and Data Monitoring Committee following completion of a prespecified futility analysis. [NuCana plc (Globe Newswire, Inc.)] Press Release

Oxurion NV Reports Topline Month 3 Results of Phase IIa Study Evaluating THR-317 (Anti-PLGF), in Combination with Ranibizumab, for DME

Oxurion NV reported topline data from a Phase IIa study evaluating THR-317, a humanized antibody against placental growth factor (PlGF), in combination with ranibizumab, an anti-vascular endothelial growth factor antibody, for the treatment of diabetic macular edema. [Oxurion NV] Press Release

Memo to Italy’s President: Your Researchers Need You

Italy’s coalition government ended abruptly, when the nationalist Lega party of deputy prime minister Matteo Salvini announced that it was walking away from its turbulent coalition with the anti-establishment M5S party, known as the Five Star Movement. The collapse is of great concern: a much-delayed funding increase is now on hold, and the political uncertainty adds further threat. [Nature News] Editorial

NSF Graduate Fellowships Disproportionately Go to Students at a Few Top Schools

As this year’s eligible students begin to labor over their applications, it’s worth asking why certain schools come away with dozens of winners each year—and what that means about the academy at large. [ScienceInsider] Editorial

DEA Again Promises to Improve Access to Marijuana for Research

Drug Enforcement Administration (DEA) announced plans to create new regulations to expand scientific and medical research on marijuana in the US. Scientists hope the proposal will allow additional growers to enter the supply chain and hopefully bump up the quality of the material. [The Scientist] Editorial

‘Paralysed by Anxiety’: Researchers Speak about Life in Troubled Ancient-DNA Lab

The University of Adelaide has suspended the leader and founder of its premier ancient-DNA center, Alan Cooper, following an investigation into the ‘culture’ at the Australian center. The university has not given a reason for its decision, but current and former co-workers of Cooper – an award-winning evolutionary biologist who specializes in human migration – have told Nature that he bullied them or that they watched him bully others. [Nature] Editorial

As Brexit Nears, Britain’s Drugs, Devices and Pricing Regulators Seek the Exit

Firm details on exactly how the UK will regulate new medicines is still to be decided after it leaves the EU later this year (caveats on timing abound), but we now know that the regulator won’t be run by Dr. Ian Hudson, who is stepping down after six years in charge. [FierceBiotech] Editorial

NEW Cell Death in Immunity and Inflamation
October 6-9, 2019
Crete, Greece

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NEW Lab Aide – Pancreatic Cancer Research (Fred Hutchinson Cancer Research Center)

Scientific Communications Coordinator (STEMCELL Technologies Inc.)

Research Technition – Diabetes, Allergies, and Lung Diseases (Helmholtz Zentrum München)

Postdoctoral Researcher – Auto-Immunity (Benaroya Research Institute)

Postdoctoral Researcher – Endocrinology, Diabetes, and Metabolism (The University of Alabama at Birmingham)

Research Scientist – Endocrine Pancreas Development (Helmholtz Zentrum München)

Research Lab Specialist – Tumor Microenvironment & Cell Behavior (University of Southern California)

Postdoctoral Fellow – Cancer Drug Response Research (University of Texas at Austin)

Postdoctoral Fellowship – Regenerative Medicine and Metabolic Biology (Indiana Biosciences Research Institute)

Research Positions – Pancreatic Beta-Cells (Université de Montréal)

Postdoctoral Fellow – Neuroscience and Diabetes (The Child Health Institute of New Jersey)

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