Intestinal Cell News Volume 5.38 | Oct 11 2019

TOP STORY

A Rectal Cancer Organoid Platform to Study Individual Responses to Chemoradiation

Researchers established a biorepository of 65 patient-derived rectal cancer (RC) organoid cultures from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients’ tumors. [Nat Med] Abstract

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Mutated CEACAMs Disrupt Transforming Growth Factor Beta Signaling and Alter the Intestinal Microbiome to Promote Colorectal Carcinogenesis

Investigators performed shotgun metagenomic sequencing analyses of feces from wild-type mice and mice with defects in transforming growth factor beta signaling to identify changes in microbiota composition before development of colon tumors. Proteins were knocked down in SW480 and HCT116 colorectal cancer cell lines, which were analyzed by immunoblotting and in proliferation and colony formation assays. [Gastroenterology] Abstract

Patient-Derived Organoids Can Predict Response to Chemotherapy in Metastatic Colorectal Cancer Patients

Scientists showed the feasibility of generating and testing patient-derived organoids (PDOs) for evaluation of sensitivity to chemotherapy. Their PDO test predicted response of the biopsied lesion in more than 80% of patients treated with irinotecan-based therapies without misclassifying patients who would have benefited from treatment. [Sci Transl Med] Abstract

5-Fluorouracil Treatment Induces Characteristic T>G Mutations in Human Cancer

The authors treated intestinal organoids with 5-Fluorouracil (5-FU) and found a highly characteristic mutational pattern that is dominated by T>G substitutions in a CTT context. Tumor whole genome sequencing data confirmed that this signature was also identified in vivo in colorectal and breast cancer patients who had received 5-FU treatment. [Nat Commun] Full Article

Dichloroacetate Restores Colorectal Cancer Chemosensitivity through the p53/miR-149-3p/PDK2-Mediated Glucose Metabolic Pathway

Researchers found that dichloroacetate markedly enhanced chemosensitivity of colorectal cancer (CRC) cells to fluorouracil (5-FU), and reduced the colony formation due to high levels of apoptosis. Using the microarray assay, they noted that miR-149-3p was involved in the chemoresistance of CRC, which was modulated by wild-type p53 after DCA treatment. [Oncogene] Full Article

Targeting Chemoresistant Colorectal Cancer via Systemic Administration of a BMP7 Variant

35 primary human cultures enriched in colorectal (CR) cancer-cancer stem cells (CRCs), including four from chemoresistant metastatic lesions, were used for in vitro studies and to generate CR-CSC-based mouse avatars to evaluate tumor growth and progression upon treatment with BMP7v alone or in combination with standard therapy or PI3K inhibitors. [Oncogene] Full Article

Oral Administration of Hydroxylated-Graphene Quantum Dots Induces Intestinal Injury Accompanying the Loss of Intestinal Stem Cells and Proliferative Progenitor Cells

Mechanistically, the hydroxylated graphene quantum dots (OH-GQDs) up-regulated both total and phosphorylated p53. Consistent with this, the average number of TUNEL⁺ and cleaved caspase-3⁺ apoptotic intestinal epithelial cells were significantly increased after OH-GQDs treatment. [Nanotoxicology] Abstract

Rev-Erbα Inhibits Proliferation by Reducing Glycolytic Flux and Pentose Phosphate Pathway in Human Gastric Cancer Cells

Knockdown of Rev-erbα significantly increased proliferation as well as glycolytic flux and the pentose phosphate pathway in human gastric cancer cells. These effects were reduced by a Rev-erbα agonist GSK4112 in a dose-dependent manner. Furthermore, Rev-erbα was recruited on the promoters of PFKFB3 and G6PD genes, thereby inhibiting their gene transcription. [Oncogenesis] Full Article

Identification of a Novel Oncogenic Mutation of FGFR4 in Gastric Cancer

Investigators report the identification of an oncogenic mutation in FGFR4 in a human gastric tumor that led to constitutive activation of its product, FGFR4. The G636C-FGFR4 tyrosine kinase domain mutation was found in 1 of 83 primary human gastric tumors. The G636C mutation increased FGFR4 autophosphorylation, and activated FGFR4 downstream signaling molecules and enhanced anchorage-independent cell growth when expressed in NIH/3T3 cells. [Sci Rep] Full Article

NSAIDs Disrupt Intestinal Homeostasis by Suppressing Macroautophagy in Intestinal Epithelial Cells

Scientists showed that non-steroidal anti-inflammatory drugs (NSAID) treatment of intestinal epithelial cells inhibited macroautophagy in vitro and in vivo. This inhibition was likely attributed to a reduction in the area and/or distribution of lysosomes available for degradation of macroautophagy-targeted cargo. [Sci Rep] Full Article

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Opinion: Are Organoids the End of Model Evolution for Studying Host Intestinal Epithelium/Microbe Interactions?

Intestinal organoids contain fully differentiated epithelial cells in the same spatial organization as in the native epithelium. The authors introduce intestinal organoids and provide some thoughts on strengths and weaknesses in the application of organoids to further advance our understanding of the intestinal epithelial-microbe relationship. [Microorganisms] Full Article

Diet, Microbiota and Colorectal Cancer

The investigators discuss how perturbation in complex regulatory networks including the Wnt, Notch, BMP and Hedgehog pathways, and how variations in inflammatory signaling, nutrients and microbiota can affect intestinal homeostasis contributing to the malignant transformation of the intestinal cells. [iScience] Abstract | Graphical Abstract

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RedHill Announces Full Results from MAP US Phase III Study and Supportive Top-Line Results from MAP US2 Study with RHB-104 in Crohn’s Disease

RedHill Biopharma Ltd. announced full Week 52 results for all subjects in the previously announced positive Phase III randomized, controlled study of RHB-104 in Crohn’s disease and supportive top-line results from the open-label extension Phase III study. [RedHill Biopharma Ltd.] Press Release

$28M Grant Funds Cincinnati Children’s as Coordinating Center for Rare Diseases Research Network

The federal agency that oversees a large network of research centers seeking cures for hundreds of rare, disabling and often fatal diseases has named Cincinnati Children’s as its new data management and coordinating center. The five-year, $28 million grant from the National Center for Advancing Translational Sciences, one of the National Institutes of Health, is among the largest ever received by Cincinnati Children’s. [Cincinnati Children’s Hospital Medical Center] Press Release

In Bid to Boost Transparency, bioRxiv Begins Posting Peer Reviews Next to Preprints

BioRxiv, the server for life sciences preprints, has begun an experiment that allows select journals and independent peer-review services to publicly post evaluations of its papers should the authors make the request. [ScienceInsider] Editorial

‘There’s No Hope for The Rest of Us.’ Uyghur Scientists Swept Up in China’s Massive Detentions

No one outside the Chinese government knows where Tashpolat Tiyip is. No one knows exactly what charges have been filed against him. The only thing that anyone really knows is that in April 2017, as the geographer and former president of Xinjiang University in Ürümqi prepared to fly from Beijing to Berlin for a scientific conference and the launch of a research center, he disappeared without even a phone call to colleagues or family. [ScienceInsider] Editorial

NEW Tumor Immunology and Immunotherapy
November 17-20, 2019
Boston, Massachusetts, United States

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NEW Assistant Professors – Microbiome Research (University of Illinois at Urbana-Champaign)

NEW Senior Scientist – Immunology and Gastroenterology (Johnson & Johnson)

NEW Research Assistant – Host-Pathogen Interaction in Intestines (The Texas Biomedical Research Institute)

Reserch Scientist – In Vivo Research on Wnt Signaling in Self-Renewel (Surrozen)

Chief Editor – Nature Ageing (Nature Research)

Postdoctoral Researcher – IBS (Quadram Institute Bioscience)

Postdoctoral Researcher – Systems Biology of Cancer (Max Planck Institute for Molecular Genetics)

Postdoctoral Fellow – Intestinal Graft-versus-Host-Disease (Medical College of Wisconsin)

Senior Researcher – Inflammatory Diseases (Genentech, Inc.)

Principal Researcher – Systems Disease Biology (Boehringer Ingelheim)

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