Intestinal Cell News Volume 3.16 | May 5 2017

TOP STORY

New Model Could Speed up Colon Cancer Research

Using the gene-editing system known as CRISPR, researchers have shown in mice that they can generate colon tumors that very closely resemble human tumors. This advance should help scientists learn more about how the disease progresses and allow them to test new therapies. [Press release from the Massachusetts Institute of Technology discussing online prepublication in Nature Biotechnology] Press Release | Abstract

(Ranked by impact factor of the journal)

INTESTINAL CANCERS & DISEASES

A Genome Editing Approach to Study Cancer Stem Cells in Human Tumors

The authors devised a strategy based on editing the genomes of patient‐derived tumor organoids using CRISPR/Cas9 technology to integrate reporter cassettes at desired marker genes. As proof of concept, they engineered human colorectal cancer organoids that carry EGFP and lineage‐tracing cassettes knocked in the LGR5 locus. [EMBO Mol Med] Full Article

Insulin Resistance in Vascular Endothelial Cells Promotes Intestinal Tumor Formation

Because hyperinsulinemia is an independent risk factor for cancer development, scientists examined tissue-specific insulin action in intestinal tumor formation. In vitro, insulin increased proliferation of intestinal tumor epithelial cells by almost two-fold in primary culture of tumor cells from Apc^Min/+ mice. [Oncogene] Abstract

The Induction of Selected Wnt Target Genes by Tcf1 Mediates Generation of Tumorigenic Colon Stem Cells

Using single-cell qPCR analysis, investigators identified a subset of Lgr5-positive stem cells that emerged during tumorigenesis in a mouse model of colon cancer. These tumor-specific Lgr5-positive cells expressed low levels of Ceacam1 and increased levels of a specific subset of Wnt targets and showed enhanced tumorigenicity. [Cell Rep] Full Article | Graphical Abstract

Epithelial Src Homology Region 2 Domain-Containing Phosphatase-1 Restrains Intestinal Growth, Secretory Cell Differentiation, and Tumorigenesis

Researchers generated mice with an intestinal epithelial cell-specific deletion of Src homology region 2 domain–containing phosphatase-1 (Shp–1). They showed that loss of epithelial Shp–1 leads to an intestinalomegaly that is associated with an increase in epithelial cell proliferation and size. [FASEB J] Abstract

RGC32 Induces Epithelial-Mesenchymal Transition by Activating the Smad/Sip1 Signaling Pathway in CRC

Scientists showed that the expression of response gene to complement 32 (RGC32) was significantly up-regulated in human colorectal cancer (CRC) tissues versus adjacent normal tissues. RGC32 expression was significantly correlated with invasive and aggressive characteristics of tumor cells, as well as poor survival of CRC patients. They demonstrated that RGC32 overexpression promoted proliferation, migration and tumorigenic growth of human CRC cells in vitro and in vivo. [Sci Rep] Full Article

INTESTINAL STEM CELL & ORGANOID RESEARCH

Transplantation of Engineered Organoids Enables Rapid Generation of Metastatic Mouse Models of Colorectal Cancer

Through the orthotopic engraftment of colon organoids, researchers describe a broadly usable immunocompetent colorectal cancer model that recapitulates the entire adenoma–adenocarcinoma–metastasis axis in vivo. The engraftment procedure takes less than five minutes, shows efficient tumor engraftment in two-thirds of mice, and can be achieved using organoids derived from genetically engineered mouse models. [Nat Biotechnol] Abstract

Non-Equivalence of Wnt and R-Spondin Ligands during Lgr5⁺ Intestinal Stem-Cell Self-Renewal

Scientists identified the functional roles of Wnt and R-spondin (RSPO) ligands in the intestinal crypt stem-cell niche. They showed that the default fate of Lgr5⁺ intestinal stem cells (ISCs) is to differentiate, unless both RSPO and Wnt ligands are present. Gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue revealed that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. [Nature] Abstract | Press Release

A Notch Positive Feedback in the Intestinal Stem Cell Niche Is Essential for Stem Cell Self‐Renewal

Investigators stimulated intestinal organoids with Notch ligands and inhibitors and discovered that intestinal stem cells employ a positive feedback mechanism via direct Notch binding to the second intron of the Notch1 gene. Inactivation of the positive feedback by CRISPR/Cas9 mutation of the binding sequence altered the mosaic stem cell niche pattern and hindered regeneration in organoids. [Mol Syst Biol] Full Article

Keratins Regulate Colonic Epithelial Cell Differentiation through the Notch1 Signaling Pathway

The authors showed that keratin (K)8 regulates Notch1 signaling activity and differentiation in the epithelium of the large intestine. Proximity ligation and immunoprecipitation assays demonstrated that K8 and Notch1 co-localized and interacted in cell cultures, and in vivo in the colonic epithelial cells. [Cell Death Differ] Full Article

Intestinal Stem Cell Pool Regulation in Drosophila

To test whether an active mechanism maintains stem cell pools in the Drosophila midgut, researchers performed partial intestinal stem cell (ISC) depletion. In contrast to the mouse intestine, Drosophila ISCs failed to repopulate the gut after partial depletion. Even when the midgut was challenged to regenerate by infection, ISCs retained normal proportions of asymmetric division and ISC pools did not increase. [Stem Cell Reports] Full Article

NSAID–Activated Gene 1 and Its Implications for Mucosal Integrity and Intervention beyond NSAIDs

The author reviews the “Yin-Yang” nature of NSAID–activated gene 1-mediated responses and provides comprehensive insights into therapeutic and diagnostic interventions for mucosal health and integrity in the human body. [Pharmacol Res] Abstract | Graphical Abstract

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

Allergan to Present New and Updated Linzess^®, Viberzi^®, Relamorelin, Linaclotide Delayed Release, and Cenicriviroc Data

Allergan plc announced that the company and its collaborators will present clinical and preclinical data for Linzess^® and linaclotide delayed release, Viberzi^®, relamorelin CIV, and cenicriviroc. [Press release from Allergan plc discussing research to be presented at Digestive Disease Week^® (DDW) 2017, Chicago] Press Release

Synergy Pharmaceuticals to Highlight New Data for Trulance^™ (Plecanatide)

Synergy Pharmaceuticals Inc. announced that the company will present six abstracts, including a late-breaker oral presentation showing new data on TRULANCE for the treatment of adults with irritable bowel syndrome with constipation. [Press release from Synergy Pharmaceuticals Inc. discussing research to be presented at Digestive Disease Week^® (DDW) 2017, Chicago] Press Release

InDex Pharmaceuticals Will Participate in the Digestive Disease Week (DDW)

InDex Pharmaceuticals Holding AB announced that the company will present two posters at the DDW. [Press release from InDex Pharmaceuticals Holding AB discussing research to be presented at Digestive Disease Week^® (DDW) 2017, Chicago] Press Release

AbbVie Demonstrates Leadership in Gastroenterology and Hepatology with New Data and Late-Breaking Studies to Be Presented

AbbVie announced that data from 20 abstracts in gastroenterology and hepatology programs will be presented. [Press release from AbbVie Inc. discussing research to be presented at Digestive Disease Week^® (DDW) 2017, Chicago] Press Release

Canadian Cancer Trials Group Awarded $23.5M over Five Years

The Canadian Cancer Society has renewed its commitment to the Canadian Cancer Trials Group (CCTG) through a major funding award of $23.5 million over five years. This generous funding allows CCTG to continue its world-class cancer clinical trials research. [Queen’s University] Press Release

George Washington (GW) Researcher Receives $1.7 Million Federal Grant to Continue Study of the Hedgehog Receptor

Among scientists specializing in the area, the mechanisms behind the signaling function of the Hedgehog (Hh) receptor pathway remain a mystery. Xiaoyen Zheng, Ph.D., assistant professor of anatomy and regenerative biology at the GW University School of Medicine and Health Sciences, who recently received a $1.7 million grant from the National Institutes of Health and National Institute of General Medical Sciences, is determined to learn more about the Hh pathway. [George Washington University] Press Release

Key Patent Issues Covering Protagonist Therapeutics’ Oral Peptide IL-23 Receptor Antagonists, including the Development Candidate PTG-200

Protagonist Therapeutics, Inc. announced that a key patent has issued covering orally stable peptide inhibitors of the interleukin-23 receptor (IL-23R), including the company’s clinical development candidate, PTG-200. The new U.S. patent provides composition of matter protection for PTG-200 and covers the use of the oral peptide inhibitors of IL-23R to treat inflammatory bowel diseases. [Protagonist Therapeutics, Inc.] Press Release

French Plan to Create €5-Billion Science ‘Super-Campus’ in Disarray

French ambitions to create a €5-billion science ‘super-campus’ near Paris by 2020 seem to be in falling further apart, after a compromise scheme to save the troubled project was rejected by one of its creators. [Nature News] Editorial

NIH Grant Limits Rile Biomedical Research Community

A decision by the US National Institutes of Health (NIH) to limit its grant support for individual researchers has sparked concerns that the policy could discourage collaboration or divert funding from the best science. The move has alarmed some researchers who agree with the NIH’s stated aim of freeing up money for young scientists, who often struggle to obtain research grants. [Nature News] Editorial

NEW Summit for Cancer Immunotherapy 2017
June 25-28, 2017
Gatineau, Canada

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

NEW Postdoctoral Research Fellow – Inflammatory Bowel Disease (Children’s Hospital Los Angeles)

NEW Senior Scientist – Gastric Oncology (Merck & Co., Inc.)

NEW Postdoctoral Research Fellow – Cancer Epidemiology (Fred Hutchinson Cancer Research Center)

Research Associate – Gastro-Intestinal Cancer (Imperial College London)

PhD Position – Colorectal Cancer (German Cancer Research Center/DKFZ)

Postdoctoral Fellow – Nanomedicine (Johns Hopkins University)

Postdoctoral and PhD Positions – Bio-Nano Science (University of South Australia)

Postdoctoral Fellow Position – Cancer Biology (Emory University)

PhD/PhD-MD Studentship – Intestinal Immunology/Immunophathobiology (Universität Bern)

Assistant or Associate Member – Stem Cell/Gene Therapy (Fred Hutchinson Cancer Research Center)

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