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colorectal organoid

Tristan Courau, Julie Bonnereau, Justine Chicoteau, Hugo Bottois, Romain Remark, Laura Assante Miranda, Antoine Toubert, Mathieu Blery, Thomas Aparicio, Matthieu Allez, Lionel Le Bourhis
BACKGROUND: Immunotherapies still fail to benefit colorectal cancer (CRC) patients. Relevant functional assays aimed at studying these failures and the efficacy of cancer immunotherapy in human are scarce. 3D tumor cultures, called tumor organoids or spheroids, represent interesting models to study cancer treatments and could help to challenge these issues. METHODS: We analyzed heterotypic cocultures of human colon tumor-derived spheroids with immune cells to assess the infiltration, activation and function of T and NK cells toward human colorectal tumors in vitro...
March 14, 2019: Journal for Immunotherapy of Cancer
Jasmin B Post, Nizar Hami, Alexander E E Mertens, Suraya Elfrink, Johannes L Bos, Hugo J G Snippert
Anti-EGFR therapy is used to treat metastatic colorectal cancer (CRC) patients, for which initial response rates of 10-20% have been achieved. Although the presence of HER2 amplifications and oncogenic mutations in KRAS, NRAS, and BRAF are associated with EGFR-targeted therapy resistance, for a large population of CRC patients the underlying mechanism of RAS-MEK-ERK hyperactivation is not clear. Loss-of-function mutations in RASGAPs are often speculated in literature to promote CRC growth as being negative regulators of RAS, but direct experimental evidence is lacking...
February 15, 2019: Oncotarget
Birgitta E Michels, Mohammed H Mosa, Britta M Grebbin, Diego Yepes, Tahmineh Darvishi, Johannes Hausmann, Henning Urlaub, Stefan Zeuzem, Hans M Kvasnicka, Thomas Oellerich, Henner F Farin
Constitutive Wnt activation upon loss of Adenoma polyposis coli ( APC ) acts as main driver of colorectal cancer (CRC). Targeting Wnt signaling has proven difficult because the pathway is crucial for homeostasis and stem cell renewal. To distinguish oncogenic from physiological Wnt activity, we have performed transcriptome and proteome profiling in isogenic human colon organoids. Culture in the presence or absence of exogenous ligand allowed us to discriminate receptor-mediated signaling from the effects of CRISPR/Cas9-induced APC loss...
February 21, 2019: Journal of Experimental Medicine
Ningning Li, Roya Babaei-Jadidi, Federica Lorenzi, Bradley Spencer-Dene, Philip Clarke, Enric Domingo, Eugene Tulchinsky, Robert G J Vries, David Kerr, Yihang Pan, Yulong He, David O Bates, Ian Tomlinson, Hans Clevers, Abdolrahman S Nateri
Colorectal cancer (CRC) patients develop recurrence after chemotherapy owing to the survival of stem cell-like cells referred to as cancer stem-like cells (CSCs). The origin of CSCs is linked to the epithelial-mesenchymal transition (EMT) process. Currently, it remains poorly understood how EMT programmes enable CSCs residing in the tumour microenvironment to escape the effects of chemotherapy. This study identifies a key molecular pathway that is responsible for the formation of drug-resistant CSC populations...
February 19, 2019: Oncogenesis
Yuhua Tian, Jiuzhi Xu, Yuan Li, Ran Zhao, Sujuan Du, Cong Lv, Wei Wu, Ruiqi Liu, Xiaole Sheng, Yongli Song, Xueyun Bi, Guilin Li, Mengzhen Li, Xi Wu, Pengbo Lou, Huiwen You, Wei Cui, Jinyue Sun, Jianwei Shuai, Fazheng Ren, Bing Zhang, Mingzhou Guo, Xiaohua Hou, Kaichun Wu, Lixiang Xue, Hongquan Zhang, Maksim V Plikus, Yingzi Cong, Christopher J Lengner, Zhanju Liu, Zhengquan Yu
BACKGROUND & AIMS: Levels of microRNA 31 (MIR31) are increased in intestinal tissues from patients with inflammatory bowel diseases and colitis-associated neoplasias. We investigated the effects of this microRNA on intestinal inflammation by studying mice with colitis. METHODS: We obtained colon biopsy samples from 82 patients with ulcerative colitis (UC), 79 patients with Crohn's disease (CD), and 34 healthy individuals (controls) at Shanghai Tenth People's Hospital...
February 16, 2019: Gastroenterology
Marco Bardenbacher, Barbara Ruder, Nathalie Britzen-Laurent, Benjamin Schmid, Maximilian Waldner, Elisabeth Naschberger, Michael Scharl, Werner Müller, Claudia Günther, Christoph Becker, Michael Stürzl, Philipp Tripal
The aberrant regulation of the epithelial barrier integrity is involved in many diseases of the digestive tract, including inflammatory bowel diseases and colorectal cancer. Intestinal epithelial cell organoid cultures provide new perspectives for analyses of the intestinal barrier in vitro. However, established methods of barrier function analyses from two dimensional cultures have to be adjusted to the analysis of three dimensional organoid structures. Here we describe the methodology for analysis of epithelial barrier function and molecular regulation in intestinal organoids...
February 7, 2019: Stem Cell Research
Thomas G Blanchard, Steven J Czinn, Vivekjyoti Banerjee, Neha Sharda, Andrea C Bafford, Fahad Mubariz, Dennis Morozov, Antonino Passaniti, Hafiz Ahmed, Aditi Banerjee
Metastatic colorectal cancer (mCRC) is characterized by the expression of cellular oncogenes, the loss of tumor suppressor gene function. Therefore, identifying integrated signaling between onco-suppressor genes may facilitate the development of effective therapy for mCRC. To investigate these pathways we utilized cell lines and patient derived organoid models for analysis of gene/protein expression, gene silencing, overexpression, and immunohistochemical analyses. An inverse relationship in expression of oncogenic FoxM1 and tumor suppressor RASSF1A was observed in various stages of CRC...
February 8, 2019: Cancers
Mizuho Sakahara, Takuya Okamoto, Jun Oyanagi, Hiroshi Takano, Yasuko Natsume, Hitomi Yamanaka, Daisuke Kusama, Mishio Fusejima, Norio Tanaka, Seiich Mori, Hiroshi Kawachi, Masashi Ueno, Yoshiharu Sakai, Tetsuo Noda, Satoshi Nagayama, Ryoji Yao
Colorectal cancer (CRC) is caused by genetic alterations, and comprehensive sequence analyses have revealed the mutation landscapes. In addition to somatic changes, genetic variations are considered important factors contributing to tumor development; however, our knowledge on this subject is limited. Familial adenomatous polyposis coli (FAP) is an autosomal-dominant inherited disease caused by germline mutations in the adenomatous polyposis coli (APC) gene. FAP patients are classified into two major groups based on clinical manifestations: classical FAP (CFAP) and attenuated FAP (AFAP)...
February 6, 2019: Cancer Science
Valentina Martin, Cristina Chiriaco, Chiara Modica, Anna Acquadro, Marco Cortese, Francesco Galimi, Timothy Perera, Loretta Gammaitoni, Massimo Aglietta, Paolo M Comoglio, Elisa Vigna, Dario Sangiolo
BACKGROUND: Interferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immune-evasion. Patients featuring MET amplification, a genetic lesion driving transformation, may benefit from anti-MET treatment. We explored if MET-targeted therapy interferes with Interferon-γ modulation of PD-L1/PD-L2 in MET-amplified tumours. METHODS: PD-L1/PD-L2 expression and signalling pathways downstream of MET or Interferon-γ were analysed in MET-amplified tumour cell lines and in patient-derived tumour organoids, in basal condition, upon Interferon-γ stimulation, and after anti-MET therapy...
February 6, 2019: British Journal of Cancer
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
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
Hui Zhao, Chang Yan, Yibing Hu, Lei Mu, Kaiyu Huang, Qiling Li, Xiaolan Li, Deding Tao, Jichao Qin
Three‑dimensional (3D) cultures are indispensable for capturing tumor heterogeneity in colorectal cancer (CRC) in vitro. Although 3D cultures (such as sphere‑forming assay and organoid culture) can partially preserve the morphological and molecular characteristics of primary CRC, whether these 3D cultures maintain the long‑term stemness of cancer stem cells (CSCs) remains largely unknown. In the present study, spheres and organoids were generated side by side using individual primary CRC specimens, then respectively processed as serial passages...
January 11, 2019: International Journal of Oncology
Sarah P Short, Joshua J Thompson, Anthony J Bilotta, Xi Chen, Frank L Revetta, M Kay Washington, Christopher S Williams
Serine Threonine Kinase 17A (STK17A) is a ubiquitously expressed kinase originally identified as a regulator of apoptosis; however, whether it functionally contributes to colorectal cancer (CRC) has not been established. Here, we have analyzed STK17A in CRC and demonstrate decreased expression of STK17A in primary tumors which is further reduced in metastatic lesions, indicating a potential role in regulating the metastatic cascade. Interestingly, changes in STK17A expression did not modify proliferation, apoptosis, or sensitivity of CRC cell lines to treatment with the chemotherapeutic 5-fluorouracil...
January 17, 2019: Molecular Cancer Research: MCR
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
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
Aki Sakatani, Fuminori Sonohara, Ajay Goel
Background: 5-fluorouracil (5-FU) has been established as the first-line chemotherapy for advanced colorectal cancer (CRC); however, acquired chemoresistance is often the cause of poor therapeutic response. Melatonin is a molecule which is associated with circadian rhythms. Although antitumor effects of melatonin have been shown, the underlying mechanism(s) for its activity and its effect, if any, in chemoresistant CRC has not been studied. We aimed to investigate antitumor effects of melatonin, and more specifically its effect on molecular mechanisms in 5-FU resistant CRC cells...
December 22, 2018: Carcinogenesis
Clément Bonamy, Emmanuel Sechet, Aurélien Amiot, Antoine Alam, Michael Mourez, Laurent Fraisse, Philippe J Sansonetti, Brice Sperandio
The human β-defensin-1 (HBD1) is an antimicrobial peptide constitutively expressed by epithelial cells at mucosal surfaces. In addition to its microbicidal properties, the loss of HBD1 expression in several cancers suggests that it may also have an anti-tumor activity. Here, we investigated the link between HBD1 expression and cancer signaling pathways in the human colon cancer cell lines TC7 and HT-29, and in normal human colonic primary cells, using a mini-gut organoid model. Using available datasets from patient cohorts, we found that HBD1 transcription is decreased in colorectal cancer...
December 21, 2018: Scientific Reports
Xin Liu, Jessica K Lukowski, Colin Flinders, Seungil Kim, Rebecca A Georgiadis, Shannon M Mumenthaler, Amanda B Hummon
Immunotherapies are treatments that use a patient's immune system to combat disease. One important type of immunotherapy employed in cancer treatments is the delivery of monoclonal antibodies to block growth receptors. In this manuscript, we develop a methodology that enables accurate and simple evaluation of antibody-type drug delivery using MALDI-MSI. To overcome the mass-range limitation that prevents the detection of large therapeutic antibodies, we used in situ reduction and alkylation to break disulfide bonds to generate smaller fragments...
December 18, 2018: Analytical Chemistry
Yuan Liu, Ye-Guang Chen
Colorectal cancer (CRC) is one of the most common cancers that have high occurrence and death in both males and females. As various factors have been found to contribute to CRC development, personalized therapies are critical for efficient treatment. To achieve this purpose, the establishment of patient-derived tumor models is critical for diagnosis and drug test. The establishment of three-dimensional (3D) organoid cultures and two-dimensional (2D) monolayer cultures of patient-derived epithelial tissues is a breakthrough for expanding living materials for later use...
November 22, 2018: Cells
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
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