Intestinal Cell News Volume 5.17 | May 17 2019

TOP STORY

MEK Inhibitors Activate Wnt Signaling and Induce Stem Cell Plasticity in Colorectal Cancer

Using large-scale compound screens in colorectal cancer (CRC), investigators identified MEK1/2 inhibitors as potent activators of Wnt/β-catenin signaling. Targeting MEK increased Wnt activity in different CRC cell lines and murine intestine in vivo. Truncating mutations of APC generated by CRISPR/Cas9 strongly synergized with MEK inhibitors in enhancing Wnt responses in isogenic CRC models. [Nat Commun] Full Article

(Ranked by impact factor of the journal)

RIP1 Inhibition Blocks Inflammatory Diseases but Not Tumor Growth or Metastases

Inhibition of RIP1 reduced collagen antibody-induced arthritis, and prevented skin inflammation caused by mutation of Sharpin, or colitis caused by deletion of Nemo from intestinal epithelial cells. Conversely, inhibition of RIP1 had no effect on tumor growth or survival in pancreatic tumor models driven by mutant Kras, nor did it reduce lung metastases in a B16 melanoma model. [Cell Death Differ] Full Article

TRAIL Suppresses Gut Inflammation and Inhibits Colitogeic T-Cell Activation in Experimental Colitis via an Apoptosis-Independent Pathway

The authors demonstrated that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) significantly suppressed gut inflammation and reduced the severity of colitis in a dextran sodium sulfate-induced colitis model. Suppression of gut inflammation was not due to induction of apoptosis in colonic T cells, dendritic cells, or epithelium cells by TRAIL. [Mucosal Immunol] Full Article

Impaired Autophagic Degradation of lncRNA ARHGAP5-AS1 Promotes Chemoresistance in Gastric Cancer

Researchers identified ARHGAP5-AS1 as a lncRNA upregulated in chemoresistant gastric cancer cells and its knockdown reversed chemoresistance. Meanwhile, high ARHGAP5-AS1 expression was associated with poor prognosis of gastric cancer patients. Intriguingly, its abundance was affected by autophagy and SQSTM1 was responsible for transporting ARHGAP5-AS1 to autophagosomes. [Cell Death Dis] Full Article

MALAT1 Regulates the Transcriptional and Translational Levels of Proto-Oncogene RUNX2 in Colorectal Cancer Metastasis

MALAT1 bound miR-15 family members, to “de-inhibit” their effect on LRP6 expression, enhancing β-catenin signaling, leading to elevated transcriptional levels of downstream target genes RUNX2. MALAT1 bound SFPQ, and dissociated SFPQ/PTBP2 dimer to release free PTBP2, which elevated translational levels of RUNX2, through interacting with IRES domain in the 5′UTR of the corresponding RUNX2 mRNAs. [Cell Death Dis] Full Article

A Short SOX9 Peptide Mimics SOX9 Tumor Suppressor Activity and Is Sufficient to Inhibit Colon Cancer Cell Growth

Investigators identified a short SOX9 sequence (S9pep) located at the hinge between the HMG DNA binding domain and the SOX-E central conserved domain that mimicked SOX9 tumor suppressor properties. Doxycycline-induced S9pep expression in DLD-1 colorectal cancer (CRC) cells inhibited the growth potential of these cells, including CRC stem cells, restored cell-cell contact inhibition, and inhibited the activity of the oncogenic Wnt/ß-catenin signaling pathway. [Mol Cancer Ther] Abstract

17-Hydroxy Wortmannin Restores TRAIL’s Response by Ameliorating Increased Beclin 1 Level and Autophagy Function in TRAIL-Resistant Colon Cancer Cells

The authors identified 17-hydroxy wortmannin (17-HW) in a drug repurposing screen that re-sensitized TNF related apoptosis-inducing ligand’s (TRAIL’s) response in resistant colon cancer cells. The deficiency of caspase-8 in drug-resistant cells along with defects in apoptotic cell death was corrected by 17-HW, an inhibitor of PIK3C3-beclin 1 complex and autophagy activity. [Mol Cancer Ther] Abstract

Short-Term 3D Culture Systems of Various Complexity for Treatment Optimization of Colorectal Carcinoma

HCT116, SW620 and DLD1 cells, cell lines with distinct mutations, grade and origin, were co-cultured with fibroblasts and endothelial cells in 3D spheroids. Clinically relevant drugs were administered individually to in CRC cell cultures. Researchers established a robust, low-cost and reproducible short-term 3D culture system addressing the various complexities of the colorectal carcinoma microenvironment. [Sci Rep] Full Article

NOD2 Agonist Murabutide Alleviates Radiation-Induced Injury through DNA Damage Response Pathway Mediated by ATR

Scientists investigated the radioprotective effects of the agonist of nucleotide-binding-oligomerization-domain-containing proteins 2 called murabutide (MBD) and clarified the potential mechanisms. Their results showed that the pretreatment with MBD effectively protected cultured cells and mice against ionizing radiation (IR)-induced toxicity and the pretreatment with MBD in vitro and in vitro also inhibited apoptosis caused by IR exposure. [J Cell Physiol] Abstract

Combination of Cetuximab and Oncolytic Virus Canerpaturev Synergistically Inhibits Human Colorectal Cancer Growth

Scientists investigated the antitumor efficacy of cetuximab, a widely used anti-EGFR monoclonal antibody, and canerpaturev (C-REV), either alone or in combination, in vitro and an in in vivo human colorectal xenograft model. In human colorectal cancer cell lines with different levels of EGFR expression, C-REV exhibited cytotoxic effects in a time- and dose-dependent manner irrespective of EGFR expression. [Mol Ther Oncolytics] Abstract

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Vitamin A and Vitamin D Regulate the Microbial Complexity, Barrier Function, and the Mucosal Immune Responses to Ensure Intestinal Homeostasis

Vitamin A- and vitamin D-mediated regulation of the intestinal epithelium and mucosal immune cells underlies the effects of these nutrients on the microbiota. Vitamin A and vitamin D regulate the expression of tight junction proteins on intestinal epithelial cells that are critical for barrier function in the gut. [Crit Rev Biochem Mol Biol] Abstract

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Metacrine to Present Relevance of FXR and Specific FXR Drug Profiles for Possible Treatment of Inflammatory Bowel Disease

Metacrine, Inc. will present data showing efficacy of M480, a potent oral non-bile acid farnesoid X receptor agonist, in multiple models of IBS. [Press release from Metacrine, Inc. discussing research to be presented at the Digestive Disease Week 2019 Annual Meeting (DDW 2019), San Diego] Press Release

17 Presentations Highlighting the Clinical Value of Cellvizio^® in Gastrointestinal Diseases

Mauna Kea Technologies announced the presentation of 17 abstracts supporting Cellvizio^®. These abstracts focus on Barrett’s esophagus, inflammatory bowel disease, food allergy, pancreatic cyst and other gastrointestinal diseases. [Press release from Mauna Kea Technologie discussing research to be presented at the Digestive Disease Week 2019 Annual Meeting (DDW 2019), San Diego] Press Release

Takeda and Frazier Healthcare Partners Announce Collaboration to Launch Phathom Pharmaceuticals

Takeda Pharmaceutical Company Limited and Frazier Healthcare Partners announced a collaboration to launch Phathom Pharmaceuticals, a biopharmaceutical company focused on the development and commercialization of novel treatments for gastrointestinal diseases and disorders. [Phantom Pharmaceuticals] Press Release

Innovation Pharmaceuticals Announces Non-Binding Term Sheet Signed with Global Pharmaceutical Company to Develop and Commercialize Brilacidin for Ulcerative Proctitis/Proctosigmoiditis

Innovation Pharmaceuticals reported that the company has signed a non-binding term sheet with a global pharmaceutical company to develop and commercialize locally-administered Brilacidin on a worldwide basis, for the treatment of ulcerative proctitis. [Innovation Pharmaceuticals, Inc.] Press Release

Parvus Therapeutics Enters into Worldwide Collaboration and License Agreement with Genentech to Develop Navacim™ Therapeutics for the Treatment of Autoimmune Diseases

Parvus Therapeutics has entered into a worldwide collaboration and license agreement with Genentech, a member of the Roche Group, to develop, manufacture, and commercialize novel Navacim™ therapeutics for the treatment of IBD, autoimmune liver diseases, and celiac disease. [Parvus Therapeutics] Press Release

Civica Rx and Xellia Pharmaceuticals Join Forces to Reduce Chronic Drug Shortages

Civica Rx and Xellia Pharmaceuticals announced they have signed a product supply agreement under which Xellia will manufacture essential antibiotics, including Vancomycin and Daptomycin, for Civica’s member health systems. Shortages of these anti-infective medications are impacting patient care in hospitals across the United States. [Civica Rx] Press Release

Landos Biopharma Announces Publication of Results from First-in-Human Phase I Study of BT-11 in Healthy Volunteers

Landos Biopharma, Inc. announced the publication of Phase I results of BT-11, its orally-active, gut-restricted investigational new drug for Crohn’s disease and ulcerative colitis, in the IBD Journal published in association with the Crohn’s & Colitis Foundation. [Landos Biopharma, Inc.] Press Release

The AGA Research Foundation Funds 52 Promising Research Projects

The American Gastroenterological Association (AGA) announced the 52 researchers selected to receive funding through the AGA Research Foundation Awards Program. The AGA Research Foundation will provide more than $3 million in research funding in the 2019 award year. [The American Association for the Advancement of Science (AAAS)] Press Release

Ford Government Scraps Funding for Stem Cell Research

The Ford government plans to stop all funding to an institute that supports Ontario scientists at the cutting edge of stem cell research. Provincial officials have told the Ontario Institute for Regenerative Medicine that its $5 million in annual funding from the province will cease next March. [CBC Radio-Canada] Editorial

Senate Panel Delays Good-Government Bill, Scolds HHS for ‘Moving the Goal Posts’

A Senate panel delayed action on a bipartisan bill to improve government transparency among advisory bodies in deference to concerns from the National Institutes of Health that the legislation would seriously disrupt the agency’s ability to review research proposals. [ScienceInsider] Editorial

To Meet the ‘Plan S’ Open-Access Mandate, Journals Mull Setting Papers Free at Publication

Plan S, the funder-backed scheme to require free online access to scientific literature, aims to shake up the subscription journals that have long dominated scholarly publishing. Now, some publishers are considering an approach they hope will both comply with the plan and maintain their subscription income: allowing authors to post manuscripts in public archives as soon as their papers are published. [ScienceInsider] Editorial

Indonesia Tops Open-Access Publishing Charts

European funders have been leading a charge under ‘Plan S’ to make more of the scientific literature free to read. Yet the nations that publish the highest proportion of their research papers open access aren’t in Europe, according to a preliminary analysis shared with Nature. [Nature News] Editorial

NEW New Advances in Inflammatory Bowel Disease Conference
September 14-15, 2019
San Diego, California, United States

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

NEW Postdoctoral Fellow – Intestinal Regenerative Medicine (Zhou Lab)

NEW Postdoctoral Fellow – Intestinal and Pulmonary Stem Cell Biology (Stanford School of Medicine)

Postdoctoral Fellow – Functional Genomics of IBS (Wellcome Sanger Institute)

Postdoctoral Researcher – Intestinal Immunology (KU Leuven)

Postdoctoral Director – mRNA Treatment for Rare Diseases (Moderna)

Postdoctoral Researcher – Gastrointestinal Cancer & IBD (Case Western Reserve University)

Postdoctoral Position – Oesophago-Gastric Cancer Research (University of Cambridge)

Postdoctoral Position – IBS and Autoimmune Disease (National Research Council of Canada)

Postdoctoral Position – Animal Genomics & IBD (University of Liège)

Graduate Student Position – Breast & Colorectal Cancer Research (Dalhousie University)

Associate Professor – Oncology (University of California, Davis)

Postdoctoral Position – Paneth Cells (Erasmus MC Cancer Institute)

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