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https://www.readbyqxmd.com/read/30109253/epithelial-smad4-deletion-up-regulates-inflammation-and-promotes-inflammation-associated-cancer
#1
Anna L Means, Tanner J Freeman, Jing Zhu, Luke G Woodbury, Paula Marincola-Smith, Chao Wu, Anne R Meyer, Connie J Weaver, Chandrasekhar Padmanabhan, Hanbing An, Jinghuan Zi, Bronson C Wessinger, Rupesh Chaturvedi, Tasia D Brown, Natasha G Deane, Robert J Coffey, Keith T Wilson, J Joshua Smith, Charles L Sawyers, James R Goldenring, Sergey V Novitskiy, M Kay Washington, Chanjuan Shi, R Daniel Beauchamp
Background & Aims: Chronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in epithelial cells, is critical for developing therapeutic interventions. Here, we explored the roles of transforming growth factor β (TGFβ) family signaling through SMAD4 in colonic epithelial cells. Methods: The Smad4 gene was deleted specifically in adult murine intestinal epithelium...
2018: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/30100188/generation-of-tumor-reactive-t-cells-by-co-culture-of-peripheral-blood-lymphocytes-and-tumor-organoids
#2
Krijn K Dijkstra, Chiara M Cattaneo, Fleur Weeber, Myriam Chalabi, Joris van de Haar, Lorenzo F Fanchi, Maarten Slagter, Daphne L van der Velden, Sovann Kaing, Sander Kelderman, Nienke van Rooij, Monique E van Leerdam, Annekatrien Depla, Egbert F Smit, Koen J Hartemink, Rosa de Groot, Monika C Wolkers, Norman Sachs, Petur Snaebjornsson, Kim Monkhorst, John Haanen, Hans Clevers, Ton N Schumacher, Emile E Voest
Cancer immunotherapies have shown substantial clinical activity for a subset of patients with epithelial cancers. Still, technological platforms to study cancer T-cell interactions for individual patients and understand determinants of responsiveness are presently lacking. Here, we establish and validate a platform to induce and analyze tumor-specific T cell responses to epithelial cancers in a personalized manner. We demonstrate that co-cultures of autologous tumor organoids and peripheral blood lymphocytes can be used to enrich tumor-reactive T cells from peripheral blood of patients with mismatch repair-deficient colorectal cancer and non-small-cell lung cancer...
August 3, 2018: Cell
https://www.readbyqxmd.com/read/30024920/modeling-apc-mutagenesis-and-familial-adenomatous-polyposis-using-human-ips-cells
#3
Cesar A Sommer, Amalia Capilla, Francisco J Molina-Estevez, Andreia Gianotti-Sommer, Nicholas Skvir, Ignacio Caballero, Sanjib Chowdhury, Gustavo Mostoslavsky
Mutations in the gene Adenomatous Polyposis Coli or APC appear in most sporadic cases of colorectal cancer and it is the most frequent mutation causing hereditary Familial Adenomatous Polyposis. The detailed molecular mechanism by which APC mutations predispose to the development of colorectal cancer is not completely understood. This is in part due to the lack of accessibility to appropriate models that recapitulate the early events associated with APC mediated intestinal transformation. We have established a novel platform utilizing human induced Pluripotent Stem cells or iPSC from normal or FAP-specific APC mutant individuals and evaluated the effect of the mutation in the cells before and after differentiation into intestinal organoids...
2018: PloS One
https://www.readbyqxmd.com/read/30017821/the-zinc-finger-transcription-factor-plagl2-enhances-stem-cell-fate-and-activates-expression-of-ascl2-in-intestinal-epithelial-cells
#4
Ashlee M Strubberg, Daniel A Veronese Paniagua, Tingting Zhao, Leeran Dublin, Thomas Pritchard, Peter O Bayguinov, James A J Fitzpatrick, Blair B Madison
Intestinal epithelial stem cell (IESC) fate is promoted by two major transcriptional regulators, the TCF4/β-catenin complex and ASCL2, which drive expression of IESC-specific factors, including Lgr5, Ephb2, and Rnf43. Canonical Wnt signaling via TCF4/β-catenin directly transactivates Ascl2, which in turn auto-regulates its own expression. Conversely, Let-7 microRNAs antagonize the IESC lineage by repressing specific mRNA targets. Here, we identify the zinc finger transcription factor PLAGL2 as a Let-7 target that regulates IESC fate...
July 9, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/30005951/the-circadian-clock-regulates-metabolic-phenotype-rewiring-via-hkdc1-and-modulates-tumor-progression-and-drug-response-in-colorectal-cancer
#5
Luise Fuhr, Rukeia El-Athman, Rosella Scrima, Olga Cela, Annalucia Carbone, Henning Knoop, Yin Li, Karen Hoffmann, Mikko O Laukkanen, Francesco Corcione, Ralf Steuer, Thomas F Meyer, Gianluigi Mazzoccoli, Nazzareno Capitanio, Angela Relógio
An endogenous molecular clockwork drives various cellular pathways including metabolism and the cell cycle. Its dysregulation is able to prompt pathological phenotypes including cancer. Besides dramatic metabolic alterations, cancer cells display severe changes in the clock phenotype with likely consequences in tumor progression and treatment response. In this study, we use a comprehensive systems-driven approach to investigate the effect of clock disruption on metabolic pathways and its impact on drug response in a cellular model of colon cancer progression...
July 2018: EBioMedicine
https://www.readbyqxmd.com/read/29985333/high-sensitivity-detection-of-micrometastases-generated-by-gfp-lentivirus-transduced-organoids-cultured-from-a-patient-derived-colon-tumor
#6
Yu Okazawa, Kosuke Mizukoshi, Yu Koyama, Shoki Okubo, Hiromitsu Komiyama, Yutaka Kojima, Michitoshi Goto, Sonoko Habu, Okio Hino, Kazuhiro Sakamoto, Akira Orimo
Despite current advances in human colorectal cancer (CRC) treatment, few radical therapies are effective for the late stages of CRC. To overcome this clinical challenge, tumor xenograft mouse models using long-established human carcinoma cell lines and many transgenic mouse models with tumors have been developed as preclinical models. They partially mimic the features of human carcinomas, but often fail to recapitulate the key aspects of human malignancies including invasion and metastasis. Thus, alternative models that better represent the malignant progression in human CRC have long been awaited...
June 14, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29980571/erbin-suppresses-ksr1-mediated-ras-raf-signaling-and-tumorigenesis-in-colorectal-cancer
#7
Payton D Stevens, Yang-An Wen, Xiaopeng Xiong, Yekaterina Y Zaytseva, Austin T Li, Chi Wang, Ashley T Stevens, Trevor N Farmer, Tong Gan, Heidi L Weiss, Masaki Inagaki, Sylvie Marchetto, Jean-Paul Borg, Tianyan Gao
Erbin belongs to the LAP (leucine-rich repeat and PDZ domain) family of scaffolding proteins that plays important roles in orchestrating cell signaling. Here we show that Erbin functions as a tumor suppressor in colorectal cancer (CRC). Analysis of Erbin expression in CRC patient specimens revealed that Erbin was downregulated at both mRNA and protein levels in tumor tissues. Knockdown of Erbin disrupted epithelial cell polarity and increased cell proliferation in 3D culture. In addition, silencing Erbin resulted in increased amplitude and duration of signaling through Akt and RAS/RAF pathways...
July 6, 2018: Cancer Research
https://www.readbyqxmd.com/read/29964038/vitamin-d-regulation-of-the-uridine-phosphorylase-1-gene-and-uridine-induced-dna-damage-in-colon-in-african-americans-and-european-americans
#8
Nobel Bhasin, Dereck Alleyne, Olivia A Gray, Sonia S Kupfer
BACKGROUND & AIMS: African Americans have the greatest colorectal cancer (CRC) burden in the United States-inter-ethnic differences in protective effects of vitamin D might contribute to disparities. 1α,25(OH)2 D3 vitamin D (the active form of vitamin D) induces transcription of the uridine phosphorylase gene (UPP1) in colon tissues from European Americans, but to a lesser extent in colon tissues from African Americans. UPP1-knockout mice have increased intestinal concentrations of uridine and dUTP, increased uridine-induced DNA damage, and develop colon tumors...
June 29, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29915160/the-endosomal-protein-cemip-links-wnt-signaling-to-mek1-erk1-2-activation-in-selumetinib-resistant-intestinal-organoids
#9
Hong-Quan Duong, Ivan Nemazanyy, Florian Rambow, Seng Chuan Tang, Sylvain Delaunay, Lars Tharun, Alexandra Florin, Reinhard Büttner, Daniel Van Daele, Pierre Close, Jean Christophe Marine, Kateryna Shostak, Alain Chariot
MAPK signaling pathways are constitutively active in colon cancer and also promote acquired resistance to MEK1 inhibition. Here we demonstrate that BRAFV600E-mutated colorectal cancers acquire resistance to MEK1 inhibition by inducing expression of the scaffold protein CEMIP through a beta-catenin- and FRA-1-dependent pathway. CEMIP was found in endosomes and bound MEK1 to sustain ERK1/2 activation in MEK1 inhibitor-resistant BRAFV600E-mutated colorectal cancers. The CEMIP-dependent pathway maintained c-Myc protein levels through ERK1/2 and provided metabolic advantage in resistant cells, potentially by sustaining amino acids synthesis...
June 18, 2018: Cancer Research
https://www.readbyqxmd.com/read/29868851/human-serum-albumin-is-an-essential-component-of-the-host-defense-mechanism-against-clostridium-difficile-intoxication
#10
Alessandra di Masi, Loris Leboffe, Fabio Polticelli, Federica Tonon, Cristina Zennaro, Marianna Caterino, Pasquale Stano, Stephan Fischer, Marlen Hägele, Martin Müller, Alexander Kleger, Panagiotis Papatheodorou, Giuseppina Nocca, Alessandro Arcovito, Andrea Gori, Margherita Ruoppolo, Holger Barth, Nicola Petrosillo, Paolo Ascenzi, Stefano Di Bella
The pathogenic effects of Clostridium difficile are primarily attributable to the production of the large protein toxins A (TcdA) and B (TcdB). These toxins monoglucosylate Rho GTPases in the cytosol of host cells, causing destruction of the actin cytoskeleton with cytotoxic effects. Low human serum albumin (HSA) levels indicate a higher risk of acquiring and developing a severe C. difficile infection (CDI) and are associated with recurrent and fatal disease. Our results show that HSA at physiological concentrations rescues human epithelial colorectal adenocarcinoma cells and protects stem cell-derived human intestinal organoids from intoxication by a TcdA:TcdB mixture...
June 2, 2018: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29844449/targeting-lgr5-in-colorectal-cancer-therapeutic-gold-or-too-plastic
#11
REVIEW
R G Morgan, E Mortensson, A C Williams
Leucine-rich repeat-containing G-protein coupled receptor (LGR5 or GPR49) potentiates canonical Wnt/β-catenin signalling and is a marker of normal stem cells in several tissues, including the intestine. Consistent with stem cell potential, single isolated LGR5+ cells from the gut generate self-organising crypt/villus structures in vitro termed organoids or 'mini-guts', which accurately model the parent tissue. The well characterised deregulation of Wnt/β-catenin signalling that occurs during the adenoma-carcinoma sequence in colorectal cancer (CRC) renders LGR5 an interesting therapeutic target...
May 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29843359/development-of-an-experimental-model-for-analyzing-drug-resistance-in-colorectal-cancer
#12
REVIEW
Mohamed Elbadawy, Tatsuya Usui, Hideyuki Yamawaki, Kazuaki Sasaki
Colorectal cancer (CRC) is one of the most common cancers, for which combination treatment of chemotherapy is employed. However, most patients develop drug resistance during the course of treatment. To clarify the mechanisms of drug resistance, various research models have been developed. Recently, we established a human CRC patients-derived three-dimensional (3D) culture system using an air-liquid interface organoid method. It contained numerous cancer stem cells and showed resistance to 5-fluorouracil and Irinotecan...
May 28, 2018: Cancers
https://www.readbyqxmd.com/read/29774115/an-improved-method-for-culturing-patient-derived-colorectal-cancer-spheroids
#13
Hiroyuki Miyoshi, Hisatsugu Maekawa, Fumihiko Kakizaki, Tadayoshi Yamaura, Kenji Kawada, Yoshiharu Sakai, M Mark Taketo
Recent advances allowed culturing and examination of patient-derived colorectal cancer (PD-CRC) cells as organoids or spheroids. To be applied to practical personalized medicine, however, current methods still need to be strengthened for higher efficiency. Here we report an improved method to propagate PD-CRC tumor initiating cells (TICs) in spheroid culture. We established > 100 cancer spheroid lines derived from independent colorectal cancer patients employing a serum-containing medium with additional inhibitors, Y27632 and SB431542...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29760071/prdm1-silences-stem-cell-related-genes-and-inhibits-proliferation-of-human-colon-tumor-organoids
#14
Changlong Liu, Carolyn E Banister, Charles C Weige, Diego Altomare, Joseph H Richardson, Carlo M Contreras, Phillip J Buckhaults
PRDM1 is a tumor suppressor that plays an important role in B and T cell lymphomas. Our previous studies demonstrated that PRDM1β is a p53-response gene in human colorectal cancer cells. However, the function of PRDM1β in colorectal cancer cells and colon tumor organoids is not clear. Here we show that PRDM1β is a p53-response gene in human colon organoids and that low PRDM1 expression predicts poor survival in colon cancer patients. We engineered PRDM1 knockouts and overexpression clones in RKO cells and characterized the PRDM1-dependent transcript landscapes, revealing that both the α and β transcript isoforms repress MYC-response genes and stem cell-related genes...
May 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29756208/impact-of-loss-of-function-mutations-at-the-rnf43-locus-on-colorectal-cancer-development-and-progression
#15
Tsugio Eto, Keisuke Miyake, Katsuhiko Nosho, Masaki Ohmuraya, Yu Imamura, Kota Arima, Shinichi Kanno, Lingfeng Fu, Yuki Kiyozumi, Daisuke Izumi, Hidetaka Sugihara, Yukiharu Hiyoshi, Yuji Miyamoto, Hiroshi Sawayama, Masaaki Iwatsuki, Yoshifumi Baba, Naoya Yoshida, Toru Furukawa, Kimi Araki, Hideo Baba, Takatsugu Ishimoto
RNF43 mutations are frequently detected in colorectal cancer cells and lead to a loss of function of the ubiquitin E3 ligase. Here, we investigated the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Mutation analysis of the RNF43 gene locus with pyrosequencing technology detected RNF43 hotspot mutations in one (0.88%) of 113 colorectal polyp cases and in 30 (6.45%) of 465 colorectal cancer cases. Moreover, patients with colorectal cancer harbouring mutated RNF43 experienced a higher recurrence rate than those harbouring non-mutated RNF43...
August 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29684110/mechanistic-insights-into-anticancer-properties-of-oligomeric-proanthocyanidins-from-grape-seeds-in-colorectal-cancer
#16
Preethi Ravindranathan, Divya Pasham, Uthra Balaji, Jacob Cardenas, Jinghua Gu, Shusuke Toden, Ajay Goel
Although the anticancer properties of oligomeric proanthocyanidins (OPCs) from grape seeds have been well recognized, the molecular mechanisms by which they exert anticancer effects are poorly understood. In this study, through comprehensive RNA-sequencing-based gene expression profiling in multiple colorectal cancer cell lines, we for the first time illuminate the genome-wide effects of OPCs from grape seeds in colorectal cancer. Our data revealed that OPCs affect several key cancer-associated genes. In particular, genes involved in cell cycle and DNA replication were most significantly and consistently altered by OPCs across multiple cell lines...
May 28, 2018: Carcinogenesis
https://www.readbyqxmd.com/read/29666172/genetic-editing-of-colonic-organoids-provides-a-molecularly-distinct-and-orthotopic-preclinical-model-of-serrated-carcinogenesis
#17
Tamsin R M Lannagan, Young K Lee, Tongtong Wang, Jatin Roper, Mark L Bettington, Lochlan Fennell, Laura Vrbanac, Lisa Jonavicius, Roshini Somashekar, Krystyna Gieniec, Miao Yang, Jia Q Ng, Nobumi Suzuki, Mari Ichinose, Josephine A Wright, Hiroki Kobayashi, Tracey L Putoczki, Yoku Hayakawa, Simon J Leedham, Helen E Abud, Ömer H Yilmaz, Julie Marker, Sonja Klebe, Pratyaksha Wirapati, Siddhartha Mukherjee, Sabine Tejpar, Barbara A Leggett, Vicki L J Whitehall, Daniel L Worthley, Susan L Woods
OBJECTIVE: Serrated colorectal cancer (CRC) accounts for approximately 25% of cases and includes tumours that are among the most treatment resistant and with worst outcomes. This CRC subtype is associated with activating mutations in the mitogen-activated kinase pathway gene, BRAF , and epigenetic modifications termed the CpG Island Methylator Phenotype, leading to epigenetic silencing of key tumour suppressor genes. It is still not clear which (epi-)genetic changes are most important in neoplastic progression and we begin to address this knowledge gap herein...
April 17, 2018: Gut
https://www.readbyqxmd.com/read/29643510/intra-tumour-diversification-in-colorectal-cancer-at-the-single-cell-level
#18
Sophie F Roerink, Nobuo Sasaki, Henry Lee-Six, Matthew D Young, Ludmil B Alexandrov, Sam Behjati, Thomas J Mitchell, Sebastian Grossmann, Howard Lightfoot, David A Egan, Apollo Pronk, Niels Smakman, Joost van Gorp, Elizabeth Anderson, Stephen J Gamble, Chris Alder, Marc van de Wetering, Peter J Campbell, Michael R Stratton, Hans Clevers
Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells...
April 2018: Nature
https://www.readbyqxmd.com/read/29642386/hedgehog-signals-mediate-anti-cancer-drug-resistance-in-three-dimensional-primary-colorectal-cancer-organoid-culture
#19
Tatsuya Usui, Masashi Sakurai, Koji Umata, Mohamed Elbadawy, Takashi Ohama, Hideyuki Yamawaki, Shoichi Hazama, Hiroko Takenouchi, Masao Nakajima, Ryouichi Tsunedomi, Nobuaki Suzuki, Hiroaki Nagano, Koichi Sato, Masahiro Kaneda, Kazuaki Sasaki
Colorectal cancer is one of the most common causes of cancer death worldwide. In patients with metastatic colorectal cancer, combination treatment with several anti-cancer drugs is employed and improves overall survival in some patients. Nevertheless, most patients with metastatic disease are not cured owing to the drug resistance. Cancer stem cells are known to regulate resistance to chemotherapy. In the previous study, we established a novel three-dimensional organoid culture model from tumor colorectal tissues of human patients using an air-liquid interface (ALI) method, which contained numerous cancer stem cells and showed resistance to 5-fluorouracil (5-FU) and Irinotecan...
April 6, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29593296/automated-brightfield-morphometry-of-3d-organoid-populations-by-organoseg
#20
Michael A Borten, Sameer S Bajikar, Nobuo Sasaki, Hans Clevers, Kevin A Janes
Spheroid and organoid cultures are powerful in vitro models for biology, but size and shape diversity within the culture is largely ignored. To streamline morphometric profiling, we developed OrganoSeg, an open-source software that integrates segmentation, filtering, and analysis for archived brightfield images of 3D culture. OrganoSeg is more accurate and flexible than existing platforms, and we illustrate its potential by stratifying 5167 breast-cancer spheroid and 5743 colon and colorectal-cancer organoid morphologies...
March 28, 2018: Scientific Reports
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