Pancreatic Cell News Volume 9.20 | May 22 2018

TOP STORY

Unresolved Endoplasmic Reticulum Stress Engenders Immune-Resistant, Latent Pancreatic Cancer Metastases

The authors created a mouse model to determine how disseminated cancer cells (DCCs) develop. Intra-portal injection of immunogenic pancreatic ductal adenocarcinoma cells into pre-immunized mice seeded livers only with single, non-replicating DCCs that were CK19^– and MHCI^–. The DCCs exhibited an endoplasmic reticulum stress response but, paradoxically lacked both inositol-requiring enzyme 1α activation and expression of the spliced form of transcription factor XBP1. [Science] Abstract | Press Release

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DIABETES & PANCREATITIS

Deficiency of PRKD2 Triggers Hyperinsulinemia and Metabolic Disorders

Investigators demonstrated that protein kinase D2 (PRKD2) deletion triggered hyperinsulinemia which preceded to insulin resistance and metabolic disorders in the PRKD2 ablation mice. PRKD2 deficiency promoted β-cell insulin secretion by increasing the expression and activity of L-type Ca²⁺ channels and subsequently augmenting high glucose- and membrane depolarization-induced Ca²⁺ influx. [Nat Commun] Full Article

LRRC8/VRAC Anion Channels Enhance β-Cell Glucose Sensing and Insulin Secretion

Researchers showed that pancreatic islets prominently expressed LRRC8A and LRRC8D, subunits of volume-regulated VRAC anion channels. Hypotonicity- or glucose-induced β-cell swelling elicited canonical LRRC8A-dependent VRAC currents that depolarized β-cells to an extent that caused electrical excitation. Glucose-induced excitation and Ca²⁺ responses were delayed in onset, but not abolished, in β-cells lacking the essential VRAC subunit LRRC8A. [Nat Commun] Full Article

Interleukin-6 Reduces β-Cell Oxidative Stress by Linking Autophagy with the Antioxidant Response

The authors showed that IL-6 couples autophagy to antioxidant response to reduce β-cell and human islet reactive oxygen species. β cell-specific loss of IL-6 signaling in vivo rendered mice more susceptible to oxidative damage and cell death by the selective β-cell toxins streptozotocin and alloxan. [Diabetes] Abstract

Ferroptosis-Inducing Agents Compromise In Vitro Human Islet Viability and Function

Viability, as assessed by lactate dehydrogenase release, revealed significant death in erastin- and RSL3-treated islets, 20.3% ± 3.8 and 24.4% ± 2.5, 24 hours post culture, respectively. These effects were ameliorated in islets pre-treated with ferrostatin-1 (Fer-1) or the iron chelator, desferrioxamine (DFO). Fer-1 and DFO pre-treatment alone did not augment islet viability or function. [Cell Death Dis] Full Article

PANCREATIC CANCER

Tuned Density of Anti-Tissue Factor Antibody Fragment onto siRNA-Loaded Polyion Complex Micelle for Optimizing Targetability into Pancreatic Cancer Cells

Researchers showed that three molecules of antibody fragment (Fab′)-installed polyion complex micelle (3(Fab′)-micelle) had the highest binding affinity to cultured pancreatic cancer BxPC3 cells, which are known to overexpress tissue factor on their surface. The 3(Fab′)-micelle also exhibited the most efficient gene silencing activity against polo-like kinase 1 mRNA in the cultured cancer cells. [Biomacromolecules] Abstract | Graphical Abstract

Axed MUC4 (MUC4/X) Aggravates Pancreatic Malignant Phenotype by Activating Integrin-β1/FAK/ERK Pathway

Doxycycline-induced expression of mucin 4 (MUC4)/X in an endogenous WT-MUC4 expressing pancreatic cancer (PC) cell line displayed enhanced cell proliferation, invasion, and adhesion to extracellular matrix, compared to WT-MUC4 alone, emphasizing its direct involvement in the aggressive behavior of cancer cells. MUC4/X facilitated PC tumorigenesis via integrin-β1/FAK/ERK signaling pathway. [Biochim Biophys Acta] Abstract

γ-Tocotrienol Induces Apoptosis in Pancreatic Cancer Cells by Upregulation of Ceramide Synthesis and Modulation of Sphingolipid Transport

γ-tocotrienol (GT3) favored the upregulation of ceramide by stimulating synthesis at the ER and the plasma membrane. The conversion of newly synthesized ceramide to sphingomyelin and glucosylceramide at the Golgi was prevented by the inhibition of CERT. Modulation of ARV1 and previously observed inhibition of the HMG-CoA pathway, contributed to changes in membrane structure and signaling functions, allowed the clustering of DR5, effectively initiating apoptosis. [BMC Cancer] Full Article

Microarray Analysis of Circular RNA Expression Profiles Associated with Gemcitabine Resistance in Pancreatic Cancer Cells

The gemcitabine (GEM)-resistant pancreatic cancer cell line, SWl990/GZ, was successfully established by treating parental SWl990 cells in vitro with increasing concentrations of GEM in culture medium intermittently for 10 months. [Oncol Rep] Abstract

PAFAH1B2 Is a HIF1a Target Gene and Promotes Metastasis in Pancreatic Cancer

Investigators reported that platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B2) was overexpressed in pancreatic ductal adenocarcinoma (PDAC) and correlated inversely with patient survival. PAFAH1B2 overexpression induced epithelial-mesenchymal transition, migration and invasion in vitro and metastasis in vivo. Silencing PAFAH1B2 inhibited these aggressive phenotypes. PAFAH1B2 overexpression in PDAC cells was directly mediated by HIF1a. [Biochem Biophys Res Commun] Full Article

Pancreas Regeneration

The leading strategy for restoration of β-cell mass is through the generation and transplantation of new β-cells derived from human pluripotent stem cells. Other approaches include stimulating endogenous β-cell proliferation, reprogramming non-β-cells to β-like cells, and harvesting islets from genetically engineered animals. Together these approaches form a rich pipeline of therapeutic development for pancreatic regeneration. [Nature] Abstract

Visit our reviews page to see a complete list of reviews in the pancreatic cell research field.

Novo Nordisk Increases Commitment to Stem Cell-Based Therapies

Novo Nordisk announced an increased commitment to stem cell-based therapies and an expansion of the focus on type 1 diabetes into other serious chronic diseases. This has been made possible through an exclusive collaboration with the University of California San Francisco in which a first milestone in the development of human embryonic stem cell lines has been reached. [Novo Nordisk A/S] Press Release

“Living Drug Factories” May One Day Replace Injections

Patients with diabetes generally rely on constant injections of insulin to control their disease. But MIT spinout Sigilon Therapeutics is developing an implantable, insulin-producing device that may one day make injections obsolete. [Massachusetts Institute of Technology] Press Release

FDA to Review Zynquista^™ (Sotagliflozin) as Potential Treatment for Type 1 Diabetes

The FDA has accepted Sanofi’s regulatory filing for Zynquista. The investigational oral treatment would be used in addition to insulin therapy to improve blood sugar control in adults with type 1 diabetes. [Sanofi-Aventis U.S. LLC] Press Release

PharmaCyte Biotech Successfully Completes 29 Tests Conducted on Live Cells Used in Pancreatic Cancer Therapy

PharmaCyte Biotech, Inc., announced that the cells it will encapsulate and then use in its planned clinical trial in patients with locally advanced, non-metastatic, inoperable pancreatic cancer have successfully passed all 29 tests required by the FDA. [PharmaCyte Biotech Inc.] Press Release

Science Needs Clarity on Europe’s Data-Protection Law

As a commendable European law on personal data comes into force, the research community must not let excessive caution about data sharing, however understandable, become the default position. [Nature News] Editorial

Indonesian Plan to Clamp Down on Foreign Scientists Draws Protest

The government’s proposals include stricter rules, and tougher penalties for researchers who break existing ones. [Nature News] Editorial

Defeated but Unbowed: Two Pennsylvania Scientists Regroup after Primary Loss

Two young scientists are picking up the pieces after Pennsylvania voters shattered their dreams of winning a seat in the U.S. House of Representatives. But neither is planning to walk away from politics. [ScienceInsider] Editorial

Congress Tees Up a Vote that Could Send ‘Right-to-Try’ Measure to Trump’s Desk

Patients with life-threatening conditions could soon have a new way to ask drug makers for medicines the FDA hasn’t yet approved, if the House is able to clear a version of “right-to-try” legislation. [STAT News] Editorial

NEW The New York Stem Cell Foundation (NYSCF) Conference
October 23-24, 2018
New York, New York, United States

Visit our events page to see a complete list of events in the community.

NEW Postdoctoral Fellow – Microfluidic Modelling of Type 2 Diabetes (Karolinska Institutet)

Director, Division of Diabetes, Endocrinology, and Metabolic Diseases (The National Institute of Diabetes & Digestive & Kidney Diseases)

Postdoctoral Scholars – Structural Biology (The University of Chicago)

Laboratory Scientific Officer/Head of Sample Processing – Type 1 Diabetes (University of Oxford)

EBPOD Fellowship – Pancreatic Cancer Analysis (European Molecular Biology Laboratory)

Postdoctoral Positions – Immunology of Diabetes (Cochin Institute)

Postdoctoral Position – Functional Genomics of Insulin Resistance (Stanford University)

Postdoctoral Fellows – Diabetes Complications & Epigenetics (St. Michael’s Hospital)

Doctoral Thesis Positions – Diabetes Research (International Helmholtz Research School for Diabetes)

Doctoral Thesis Position – Genomics of Pancreatic Cancer and Pancreatic Development (Universitatsklinikum Ulm)

Associate Professor or Professor – Biomedical Metabolics (The Ohio State University Wexner Medical Center)

Postdoctoral Scholar – Glucose Homeostasis, Obesity & Type 2 Diabetes (University of California – San Francisco)

Postdoctoral Fellow – Molecular Medicine (City of Hope)

Doctoral Thesis Position – Endocrine Cell Research (Helmholtz Zentrum Munchen)

Doctoral Thesis Position – Diabetes Research (Universite Libre de Bruxelles)

Postdoctoral Fellow – Beta Cell Research (Helmholtz Zentrum Munchen – German Reserach Center for Environmental Health)

Director, Division of Extramural Activities – Diabetes, Digestive and Kidney Diseases (National Institutes of Health)

Postdoctoral Fellow – Pancreatic Cancer Research (University of New South Wales)

Pioneer Award Postdoctoral Fellowships – Pancreatic Cancer (University of Miami Miller School of Medicine)

Postdoctoral Position – Inflammation and Metabolism (Sanford Burnham Prebys Medical Discovery Institute)

Research Fellow/Associate – Diabetes Research (Rutgers University)

Postdoctoral Scholar – Cancer (University of California, San Francisco)

Postdoctoral Fellow – Epigenetic Regulation of Pancreatic Beta-Cell Mass (City of Hope)

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