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https://read.qxmd.com/read/30753828/aging-like-spontaneous-epigenetic-silencing-facilitates-wnt-activation-stemness-and-braf-v600e-induced-tumorigenesis
#1
Yong Tao, Byunghak Kang, Daniel A Petkovich, Yuba R Bhandari, Julie In, Genevieve Stein-O'Brien, Xiangqian Kong, Wenbing Xie, Nicholas Zachos, Shinji Maegawa, Himani Vaidya, Stephen Brown, Ray-Whay Chiu Yen, Xiaojian Shao, Jai Thakor, Zhihao Lu, Yi Cai, Yuezheng Zhang, Izaskun Mallona, Miguel Angel Peinado, Cynthia A Zahnow, Nita Ahuja, Elana Fertig, Jean-Pierre Issa, Stephen B Baylin, Hariharan Easwaran
We addressed the precursor role of aging-like spontaneous promoter DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show that promoter hypermethylation spontaneously arises in cells mimicking the human aging-like phenotype. The silenced genes activate the Wnt pathway, causing a stem-like state and differentiation defects. These changes render aged organoids profoundly more sensitive than young ones to transformation by BrafV600E , producing the typical human proximal BRAFV600E -driven colon adenocarcinomas characterized by extensive, abnormal gene-promoter CpG-island methylation, or the methylator phenotype (CIMP)...
February 11, 2019: Cancer Cell
https://read.qxmd.com/read/30704978/genome-wide-epigenetic-and-transcriptomic-characterization-of-human-induced-pluripotent-stem-cell-derived-intestinal-epithelial-organoids
#2
Judith Kraiczy, Alexander D B Ross, Jessica L Forbester, Gordon Dougan, Ludovic Vallier, Matthias Zilbauer
No abstract text is available yet for this article.
October 23, 2018: Cellular and Molecular Gastroenterology and Hepatology
https://read.qxmd.com/read/30679179/ido1-and-kynurenine-pathway-metabolites-activate-pi3k-akt-signaling-in-the-neoplastic-colon-epithelium-to-promote-cancer-cell-proliferation-and-inhibit-apoptosis
#3
Kumar S Bishnupuri, David M Alvarado, Alexander N Khouri, Mark Shabsovich, Baosheng Chen, Brian K Dieckgraefe, Matthew A Ciorba
The tryptophan-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) is frequently overexpressed in epithelial-derived malignancies, where it plays a recognized role in promoting tumor immune tolerance. We previously demonstrated that the IDO1-kynurenine pathway (KP) also directly supports colorectal cancer (CRC) growth by promoting activation of β-catenin and driving neoplastic growth in mice lacking intact adaptive immunity. In this study, we sought to delineate the specific role of epithelial IDO1 in colon tumorigenesis and define how IDO1 and KP metabolites interact with pivotal neoplastic signaling pathways of the colon epithelium...
January 24, 2019: Cancer Research
https://read.qxmd.com/read/30679176/pleiotropic-effects-of-ppard-accelerate-colorectal-tumorigenesis-progression-and-invasion
#4
Yi Liu, Yasunori Deguchi, Rui Tian, Daoyan Wei, Ling Wu, Weidong Chen, Weiguo Xu, Min Xu, Fuyao Liu, Shen Gao, Jonathan C Jaoude, Sarah P Chrieki, Micheline J Moussalli, Mihai Gagea, Jeffrey Morris, Russell R Broaddus, Xiangsheng Zuo, Imad Shureiqi
APC mutations activate aberrant β-catenin signaling to drive initiation of colorectal cancer (CRC), however, CRC progression requires additional molecular mechanisms. PPAR-delta (PPARD), a downstream target of β-catenin, is upregulated in CRC. However, promotion of intestinal tumorigenesis following deletion of PPARD in Apcmin mice has raised questions about the effects of PPARD on aberrant β-catenin activation and CRC. In this study, we used mouse models of PPARD overexpression or deletion combined with APC mutation (ApcΔ580) in intestinal epithelial cells (IEC) to elucidate the contributions of PPARD in CRC...
January 24, 2019: Cancer Research
https://read.qxmd.com/read/30655563/human-tnf-luc-reporter-mouse-a-new-model-to-quantify-inflammatory-responses
#5
Faisal Minshawi, Mike R H White, Werner Muller, Neil Humphreys, Dean Jackson, Barry J Campbell, Antony Adamson, Stamatia Papoutsopoulou
Tumour necrosis factor (TNF) is a key cytokine during inflammatory responses and its dysregulation is detrimental in many inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. Here, we used a bacterial artificial chromosome (BAC) construct that expresses luciferase under the control of the human TNF locus to generate a novel transgenic mouse, the hTNF.LucBAC strain. In vitro stimulation of hTNF.LucBAC cells of different origin revealed a cell specific response to stimuli demonstrating the integrated construct's ability as a proxy for inflammatory gene response...
January 17, 2019: Scientific Reports
https://read.qxmd.com/read/30637899/shortcuts-to-intestinal-carcinogenesis-by-genetic-engineering-in-organoids
#6
REVIEW
Yoshiaki Maru, Kunishige Onuma, Masako Ochiai, Toshio Imai, Yoshitaka Hippo
Inactivation of the Adenomatous Polyposis Coli (APC) gene is an initiating and the most relevant event in the majority of sporadic cases with colorectal cancer, providing a rationale for using Apc-mutant mice as the disease model. Whereas carcinogenesis has been observed only at the organism level, the recent development of organoid culture technique has enabled long-term propagation of intestinal stem cells in a physiological setting, raising the possibility that organoids could serve as an alternative platform for modeling colon carcinogenesis...
January 13, 2019: Cancer Science
https://read.qxmd.com/read/30622113/frizzled-7-is-required-for-wnt-signaling-in-gastric-tumors-with-and-without-apc-mutations
#7
Dustin Flanagan, Nick Barker, Natasha S Di Costanzo, Elizabeth Anne Mason, Austin Gurney, Valerie S Meniel, Sarah Koushyar, Chloe R Austin, Helen B Pearson, Alex Boussioutas, Hans Clevers, Toby J Phesse, Elisabeth Vincan
A subset of gastric cancer (GC) patients have mutations in genes that participate in or regulate Wnt signaling at the level of ligand (Wnt) receptor (Fzd) binding. Moreover, increased Fzd expression is associated with poor clinical outcome. Despite these findings, there are no in vivo studies investigating the potential of targeting Wnt receptors for treating GC, and the specific Wnt receptor transmitting oncogenic Wnt signaling in GC is unknown. Here we use inhibitors of Wnt/Fzd (OMP-18R5/Vantictumab) and conditional gene deletion to test the therapeutic potential of targeting Wnt signaling in preclinical models of intestinal-type gastric cancer and ex vivo organoid cultures...
January 8, 2019: Cancer Research
https://read.qxmd.com/read/30612954/nonadhesive-alginate-hydrogels-support-growth-of-pluripotent-stem-cell-derived-intestinal-organoids
#8
Meghan M Capeling, Michael Czerwinski, Sha Huang, Yu-Hwai Tsai, Angeline Wu, Melinda S Nagy, Benjamin Juliar, Nambirajan Sundaram, Yang Song, Woojin M Han, Shuichi Takayama, Eben Alsberg, Andres J Garcia, Michael Helmrath, Andrew J Putnam, Jason R Spence
Human intestinal organoids (HIOs) represent a powerful system to study human development and are promising candidates for clinical translation as drug-screening tools or engineered tissue. Experimental control and clinical use of HIOs is limited by growth in expensive and poorly defined tumor-cell-derived extracellular matrices, prompting investigation of synthetic ECM-mimetics for HIO culture. Since HIOs possess an inner epithelium and outer mesenchyme, we hypothesized that adhesive cues provided by the matrix may be dispensable for HIO culture...
December 19, 2018: Stem Cell Reports
https://read.qxmd.com/read/30599053/establishment-of-a-system-to-evaluate-the-therapeutic-effect-and-the-dynamics-of-an-investigational-drug-on-ulcerative-colitis-using-human-colonic-organoids
#9
Ryu Nishimura, Tomoaki Shirasaki, Kiichiro Tsuchiya, Yoshihide Miyake, Yusuke Watanabe, Shuji Hibiya, Sho Watanabe, Tetsuya Nakamura, Mamoru Watanabe
BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with an intractable, recurrent course. The goal of UC therapy is to target mucosal healing because immune-suppressive therapy for UC frequently results in relapse. However, few drugs directly target mucosal healing. We, therefore, aim to evaluate the therapeutic effect of an investigational drug on intestinal epithelial cells in an in vitro UC model using human colonic organoids. METHODS: Colonic organoids were isolated from human colon and cultured...
January 1, 2019: Journal of Gastroenterology
https://read.qxmd.com/read/30599048/a-c-ebp%C3%AE-wnt-connection-in-gut-homeostasis-and-carcinogenesis
#10
Julian Heuberger, Undine Hill, Susann Förster, Karin Zimmermann, Victoria Malchin, Anja A Kühl, Ulrike Stein, Michael Vieth, Walter Birchmeier, Achim Leutz
We explored the connection between C/EBPα (CCAAT/enhancer-binding protein α) and Wnt signaling in gut homeostasis and carcinogenesis. C/EBPα was expressed in human and murine intestinal epithelia in the transit-amplifying region of the crypts and was absent in intestinal stem cells and Paneth cells with activated Wnt signaling. In human colorectal cancer and murine APCMin/+ polyps, C/EBPα was absent in the nuclear β-catenin-positive tumor cells. In chemically induced intestinal carcinogenesis, C/EBPα KO in murine gut epithelia increased tumor volume...
February 2019: Life science alliance
https://read.qxmd.com/read/30591184/primary-cell-derived-intestinal-models-recapitulating-physiology
#11
REVIEW
Johanna S Dutton, Samuel S Hinman, Raehyun Kim, Yuli Wang, Nancy L Allbritton
The development of physiologically relevant intestinal models fueled by breakthroughs in primary cell-culture methods has enabled successful recapitulation of key features of intestinal physiology. These advances, paired with engineering methods, for example incorporating chemical gradients or physical forces across the tissues, have yielded ever more sophisticated systems that enhance our understanding of the impact of the host microbiome on human physiology as well as on the genesis of intestinal diseases such as inflammatory bowel disease and colon cancer...
December 24, 2018: Trends in Biotechnology
https://read.qxmd.com/read/30581387/human-primary-epithelial-cell-models-promising-tools-in-the-era-of-cystic-fibrosis-personalized-medicine
#12
REVIEW
Nikhil T Awatade, Sharon L Wong, Chris K Hewson, Laura K Fawcett, Anthony Kicic, Adam Jaffe, Shafagh A Waters
Cystic fibrosis (CF) is an inherited disorder where individual disease etiology and response to therapeutic intervention is impacted by CF transmembrane regulator (CFTR) mutations and other genetic modifiers. CFTR regulates multiple mechanisms in a diverse range of epithelial tissues. In this Review, we consolidate the latest updates in the development of primary epithelial cellular model systems relevant for CF. We discuss conventional two-dimensional (2-D) airway epithelial cell cultures, the backbone of in vitro cellular models to date, as well as improved expansion protocols to overcome finite supply of the cellular source...
2018: Frontiers in Pharmacology
https://read.qxmd.com/read/30526881/human-intestinal-organoids-maintain-self-renewal-capacity-and-cellular-diversity-in-niche-inspired-culture-condition
#13
Masayuki Fujii, Mami Matano, Kohta Toshimitsu, Ai Takano, Yohei Mikami, Shingo Nishikori, Shinya Sugimoto, Toshiro Sato
Cellular diversity that shapes tissue architecture and function is governed by multiple niche signals. Nonetheless, maintaining cellular diversity in human intestinal organoids has been challenging. Based on niche ligands present in the natural stem cell milieu, we establish a refined organoid culture condition for intestinal epithelia that allows human intestinal organoids to concurrently undergo multi-differentiation and self-renewal. High-throughput screening reveals that the combination of insulin-like growth factor 1 (IGF-1) and fibroblast growth factor 2 (FGF-2) enhances the clonogenic capacity and CRISPR-genome engineering efficiency of human intestinal stem cells...
December 6, 2018: Cell Stem Cell
https://read.qxmd.com/read/30521806/small-heterodimer-partner-and-fibroblast-growth-factor-19-inhibit-expression-of-npc1l1-in-mouse-intestine-and-cholesterol-absorption
#14
Young-Chae Kim, Sangwon Byun, Sunmi Seok, Grace Guo, H Eric Xu, Byron Kemper, Jongsook Kim Kemper
BACKGROUND & AIMS: The nuclear receptor subfamily 0 group B member 2 (NR0B2, also called SHP) is expressed at high levels in liver and intestine. Postprandial fibroblast growth factor 19 (human FGF19, mouse FGF15) signaling increases the transcriptional activity of SHP. We studied the functions of SHP and FGF19 in intestines of mice, including their regulation of expression of the cholesterol transporter NPC1-like intracellular cholesterol transporter 1 (NPC1L1) and cholesterol absorption...
December 3, 2018: Gastroenterology
https://read.qxmd.com/read/30504008/high-throughput-single-cell-transcriptomics-on-organoids
#15
REVIEW
Agnieska Brazovskaja, Barbara Treutlein, J Gray Camp
Three-dimensional (3D) tissues grown in culture from human stem cells offer the incredible opportunity to analyze and manipulate human development, and to generate patient-specific models of disease. Methods to sequence DNA and RNA in single cells are being used to analyze these so-called 'organoid' systems in high-resolution. Single-cell transcriptomics has been used to quantitate the similarity of organoid cells to primary tissue counterparts in the brain, intestine, liver, and kidney, as well as identify cell-specific responses to environmental variables and disease conditions...
November 29, 2018: Current Opinion in Biotechnology
https://read.qxmd.com/read/30488522/the-effect-of-premature-termination-codon-mutations-on-cftr-mrna-abundance-in-human-nasal-epithelium-and-intestinal-organoids-a-basis-for-read-through-therapies-in-cystic-fibrosis
#16
Luka A Clarke, Nikhil T Awatade, Veronica M Felício, Iris A Silva, Maite Calucho, Luisa Pereira, Pilar Azevedo, José Cavaco, Celeste Barreto, Carmen Bertuzzo, Silvia Gartner, Jeffrey Beekman, Margarida D Amaral
A major challenge in cystic fibrosis (CF) research is applying mutation-specific therapy to individual patients with diverse and rare CF transmembrane conductance regulator (CFTR) genotypes. Read-through agents are currently the most promising approach for Class I mutations that introduce premature termination codons (PTCs) into CFTR mRNA. However, variations in degradation of PTC containing transcripts by nonsense mediated decay (NMD) might lower read-through efficacy. Allele specific quantitative real time (qRT)-PCR was used to measure variations in CFTR mRNA abundance for several PTC mutations in respiratory cells and intestinal organoids...
November 28, 2018: Human Mutation
https://read.qxmd.com/read/30478383/dclk1-in-tuft-cells-promotes-inflammation-driven-epithelial-restitution-and-mitigates-chronic-colitis
#17
Jun Yi, Kirk Bergstrom, Jianxin Fu, Xindi Shan, J Michael McDaniel, Samuel McGee, Dongfeng Qu, Courtney W Houchen, Xiaowei Liu, Lijun Xia
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by defective intestinal barrier integrity toward the microbiota and epithelial damage. Double cortin-like kinase 1 (Dclk1), a marker of intestinal tuft cells, can regulate tissue regenerative responses, but its role in epithelial repair during bacterial-dependent chronic colitis is unclear. We addressed this question using our recently developed mouse model of spontaneous microbiota-dependent colitis induced by mucin-type O-glycan deficiency (DKO), which recapitulates most features of human UC...
November 26, 2018: Cell Death and Differentiation
https://read.qxmd.com/read/30478287/an-upstream-protein-coding-region-in-enteroviruses-modulates-virus-infection-in-gut-epithelial-cells
#18
Valeria Lulla, Adam M Dinan, Myra Hosmillo, Yasmin Chaudhry, Lee Sherry, Nerea Irigoyen, Komal M Nayak, Nicola J Stonehouse, Matthias Zilbauer, Ian Goodfellow, Andrew E Firth
Enteroviruses comprise a large group of mammalian pathogens that includes poliovirus. Pathology in humans ranges from sub-clinical to acute flaccid paralysis, myocarditis and meningitis. Until now, all of the enteroviral proteins were thought to derive from the proteolytic processing of a polyprotein encoded in a single open reading frame. Here we report that many enterovirus genomes also harbour an upstream open reading frame (uORF) that is subject to strong purifying selection. Using echovirus 7 and poliovirus 1, we confirmed the expression of uORF protein in infected cells...
November 26, 2018: Nature Microbiology
https://read.qxmd.com/read/30465020/nhe8-deficiency-promotes-colitis-associated-cancer-in-mice-via-expansion-of-lgr5-expressing-cells
#19
Hua Xu, Jing Li, Hao Chen, Fayez K Ghishan
Background & Aims: Lgr5 overexpression has been detected in colorectal cancers (CRCs), including some cases of colitis-associated CRCs. In colitis-associated CRCs, chronic inflammation is a contributing factor in carcinogenesis. We recently reported that intestinal Na+ /H+ exchanger isoform 8 (NHE8) plays an important role in intestinal mucosal protection and that loss of NHE8 expression results in an ulcerative colitis-like condition. Therefore, we hypothesized that NHE8 may be involved in the development of intestinal tumors...
2019: Cellular and Molecular Gastroenterology and Hepatology
https://read.qxmd.com/read/30443904/organ-on-chip-models-implications-in-drug-discovery-and-clinical-applications
#20
REVIEW
Rahul Mittal, Frank W Woo, Carlo S Castro, Madeline A Cohen, Joana Karanxha, Jeenu Mittal, Tanya Chhibber, Vasanti M Jhaveri
Before a lead compound goes through a clinical trial, preclinical studies utilize two-dimensional (2D) in vitro models and animal models to study the pharmacodynamics and pharmacokinetics of that lead compound. However, these current preclinical studies may not accurately represent the efficacy and safety of a lead compound in humans, as there has been a high failure rate of drugs that enter clinical trials. All of these failures and the associated costs demonstrate a need for more representative models of human organ systems for screening in the preclinical phase of drug development...
November 15, 2018: Journal of Cellular Physiology
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