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https://www.readbyqxmd.com/read/27869803/genome-wide-crispr-screens-reveal-a-wnt-fzd5-signaling-circuit-as-a-druggable-vulnerability-of-rnf43-mutant-pancreatic-tumors
#1
Zachary Steinhart, Zvezdan Pavlovic, Megha Chandrashekhar, Traver Hart, Xiaowei Wang, Xiaoyu Zhang, Mélanie Robitaille, Kevin R Brown, Sridevi Jaksani, René Overmeer, Sylvia F Boj, Jarrett Adams, James Pan, Hans Clevers, Sachdev Sidhu, Jason Moffat, Stéphane Angers
Forward genetic screens with CRISPR-Cas9 genome editing enable high-resolution detection of genetic vulnerabilities in cancer cells. We conducted genome-wide CRISPR-Cas9 screens in RNF43-mutant pancreatic ductal adenocarcinoma (PDAC) cells, which rely on Wnt signaling for proliferation. Through these screens, we discovered a unique requirement for a Wnt signaling circuit: engaging FZD5, one of the ten Frizzled receptors encoded in the human genome. Our results uncover an underappreciated level of context-dependent specificity at the Wnt receptor level...
November 21, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27851739/designer-matrices-for-intestinal-stem-cell-and-organoid-culture
#2
Nikolce Gjorevski, Norman Sachs, Andrea Manfrin, Sonja Giger, Maiia E Bragina, Paloma Ordóñez-Morán, Hans Clevers, Matthias P Lutolf
Epithelial organoids recapitulate multiple aspects of real organs, making them promising models of organ development, function and disease. However, the full potential of organoids in research and therapy has remained unrealized, owing to the poorly defined animal-derived matrices in which they are grown. Here we used modular synthetic hydrogel networks to define the key extracellular matrix (ECM) parameters that govern intestinal stem cell (ISC) expansion and organoid formation, and show that separate stages of the process require different mechanical environments and ECM components...
November 16, 2016: Nature
https://www.readbyqxmd.com/read/27845624/targeting-mutant-ras-in-patient-derived-colorectal-cancer-organoids-by-combinatorial-drug-screening
#3
Carla S Verissimo, René M Overmeer, Bas Ponsioen, Jarno Drost, Sander Mertens, Ingrid Verlaan-Klink, Bastiaan van Gerwen, Marieke van der Ven, Marc van de Wetering, David A Egan, René Bernards, Hans Clevers, Johannes L Bos, Hugo J Snippert
Colorectal cancer (CRC) organoids can be derived from almost all CRC patients and therefore capture the genetic diversity of this disease. We assembled a panel of CRC organoids carrying either wild-type or mutant RAS, as well as normal organoids and tumor organoids with a CRISPR-introduced oncogenic KRAS mutation. Using this panel, we evaluated RAS pathway inhibitors and drug combinations that are currently in clinical trial for RAS mutant cancers. Presence of mutant RAS correlated strongly with resistance to these targeted therapies...
November 15, 2016: ELife
https://www.readbyqxmd.com/read/27802133/regulation-and-plasticity-of-intestinal-stem-cells-during-homeostasis-and-regeneration
#4
REVIEW
Joep Beumer, Hans Clevers
The intestinal epithelium is the fastest renewing tissue in mammals and has a large flexibility to adapt to different types of damage. Lgr5(+) crypt base columnar (CBC) cells act as stem cells during homeostasis and are essential during regeneration. Upon perturbation, the activity of CBCs is dynamically regulated to maintain homeostasis and multiple dedicated progenitor cell populations can reverse to the stem cell state upon damage, adding another layer of compensatory mechanisms to facilitate regeneration...
October 15, 2016: Development
https://www.readbyqxmd.com/read/27776108/programs-for-the-persistence-vigilance-and-control-of-human-cd8-lung-resident-memory-t-cells
#5
Pleun Hombrink, Christina Helbig, Ronald A Backer, Berber Piet, Anna E Oja, Regina Stark, Giso Brasser, Aldo Jongejan, René E Jonkers, Benjamin Nota, Onur Basak, Hans C Clevers, Perry D Moerland, Derk Amsen, René A W van Lier
Tissue-resident memory T cells (TRM cells) in the airways mediate protection against respiratory infection. We characterized TRM cells expressing integrin αE (CD103) that reside within the epithelial barrier of human lungs. These cells had specialized profiles of chemokine receptors and adhesion molecules, consistent with their unique localization. Lung TRM cells were poised for rapid responsiveness by constitutive expression of deployment-ready mRNA encoding effector molecules, but they also expressed many inhibitory regulators, suggestive of programmed restraint...
December 2016: Nature Immunology
https://www.readbyqxmd.com/read/27708166/generation-of-an-inducible-colon-specific-cre-enzyme-mouse-line-for-colon-cancer-research
#6
Paul W Tetteh, Kai Kretzschmar, Harry Begthel, Maaike van den Born, Jeroen Korving, Folkert Morsink, Henner Farin, Johan H van Es, G Johan A Offerhaus, Hans Clevers
Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic anhydrase I (Car1) is a gene expressed uniquely in colonic epithelial cells. We generated a colon-specific inducible Car1(CreER) knock-in (KI) mouse with broad Cre activity in epithelial cells of the proximal colon and cecum...
October 18, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27698416/tissue-specific-mutation-accumulation-in-human-adult-stem-cells-during-life
#7
Francis Blokzijl, Joep de Ligt, Myrthe Jager, Valentina Sasselli, Sophie Roerink, Nobuo Sasaki, Meritxell Huch, Sander Boymans, Ewart Kuijk, Pjotr Prins, Isaac J Nijman, Inigo Martincorena, Michal Mokry, Caroline L Wiegerinck, Sabine Middendorp, Toshiro Sato, Gerald Schwank, Edward E S Nieuwenhuis, Monique M A Verstegen, Luc J W van der Laan, Jeroen de Jonge, Jan N M IJzermans, Robert G Vries, Marc van de Wetering, Michael R Stratton, Hans Clevers, Edwin Cuppen, Ruben van Boxtel
The gradual accumulation of genetic mutations in human adult stem cells (ASCs) during life is associated with various age-related diseases, including cancer. Extreme variation in cancer risk across tissues was recently proposed to depend on the lifetime number of ASC divisions, owing to unavoidable random mutations that arise during DNA replication. However, the rates and patterns of mutations in normal ASCs remain unknown. Here we determine genome-wide mutation patterns in ASCs of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years by sequencing clonal organoid cultures derived from primary multipotent cells...
October 3, 2016: Nature
https://www.readbyqxmd.com/read/27676432/organoids-modeling-development-and-the-stem-cell-niche-in-a-dish
#8
REVIEW
Kai Kretzschmar, Hans Clevers
Organoids are three-dimensional in-vitro-grown cell clusters with near-native microanatomy that arise from self-organizing mammalian pluripotent or adult stem cells. Although monolayer stem cell cultures were established more than 40 years ago, organoid technology has recently emerged as an essential tool for both fundamental and biomedical research. For developmental biologists, organoids provide powerful means for ex vivo modeling of tissue morphogenesis and organogenesis. Here we discuss how organoid cultures of the intestine and other tissues have been established and how they are utilized as an in vitro model system for stem cell research and developmental biology...
September 26, 2016: Developmental Cell
https://www.readbyqxmd.com/read/27590160/the-generation-of-organoids-for-studying-wnt-signaling
#9
Jarno Drost, Benedetta Artegiani, Hans Clevers
We established an in vitro culture model in which intestinal epithelial stem cells can grow into three-dimensional, ever-expanding epithelial organoids that retain their original organ identity and genetic stability. Moreover, organoids can easily be genetically modified using different genome modification strategies, including viral delivery of transgenes and CRISPR/Cas9 technology. These combined characteristics make them a useful in vitro model system to study many biological processes including the contribution of cellular signaling pathways to tissue homeostasis and disease...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27573849/reg4-deep-crypt-secretory-cells-function-as-epithelial-niche-for-lgr5-stem-cells-in-colon
#10
Nobuo Sasaki, Norman Sachs, Kay Wiebrands, Saskia I J Ellenbroek, Arianna Fumagalli, Anna Lyubimova, Harry Begthel, Maaike van den Born, Johan H van Es, Wouter R Karthaus, Vivian S W Li, Carmen López-Iglesias, Peter J Peters, Jacco van Rheenen, Alexander van Oudenaarden, Hans Clevers
Leucine-rich repeat-containing G-protein coupled receptor 5-positive (Lgr5(+)) stem cells reside at crypt bottoms of the small and large intestine. Small intestinal Paneth cells supply Wnt3, EGF, and Notch signals to neighboring Lgr5(+) stem cells. Whereas the colon lacks Paneth cells, deep crypt secretory (DCS) cells are intermingled with Lgr5(+) stem cells at crypt bottoms. Here, we report regenerating islet-derived family member 4 (Reg4) as a marker of DCS cells. To investigate a niche function, we eliminated DCS cells by using the diphtheria-toxin receptor gene knocked into the murine Reg4 locus...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27560176/culture-and-establishment-of-self-renewing-human-and-mouse-adult-liver-and-pancreas-3d-organoids-and-their-genetic-manipulation
#11
Laura Broutier, Amanda Andersson-Rolf, Christopher J Hindley, Sylvia F Boj, Hans Clevers, Bon-Kyoung Koo, Meritxell Huch
Adult somatic tissues have proven difficult to expand in vitro, largely because of the complexity of recreating appropriate environmental signals in culture. We have overcome this problem recently and developed culture conditions for adult stem cells that allow the long-term expansion of adult primary tissues from small intestine, stomach, liver and pancreas into self-assembling 3D structures that we have termed 'organoids'. We provide a detailed protocol that describes how to grow adult mouse and human liver and pancreas organoids, from cell isolation and long-term expansion to genetic manipulation in vitro...
September 2016: Nature Protocols
https://www.readbyqxmd.com/read/27558455/inactivation-of-tgf%C3%AE-receptors-in-stem-cells-drives-cutaneous-squamous-cell-carcinoma
#12
Patrizia Cammareri, Aidan M Rose, David F Vincent, Jun Wang, Ai Nagano, Silvana Libertini, Rachel A Ridgway, Dimitris Athineos, Philip J Coates, Angela McHugh, Celine Pourreyron, Jasbani H S Dayal, Jonas Larsson, Simone Weidlich, Lindsay C Spender, Gopal P Sapkota, Karin J Purdie, Charlotte M Proby, Catherine A Harwood, Irene M Leigh, Hans Clevers, Nick Barker, Stefan Karlsson, Catrin Pritchard, Richard Marais, Claude Chelala, Andrew P South, Owen J Sansom, Gareth J Inman
Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF/MAPK pathway activation. Here we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFβ Smad signalling, which is localized to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through Braf(V600E) or Kras(G12D) knockin) and TGFβ signalling ablation (through Tgfbr1 deletion) in LGR5(+ve) stem cells enables rapid cSCC development in the mouse...
August 25, 2016: Nature Communications
https://www.readbyqxmd.com/read/27505425/cell-scientist-to-watch-meritxell-huch
#13
(no author information available yet)
After completing her BSc in pharmacology at University of Barcelona, Spain, Meritxell Huch pursued her PhD in the laboratory of Cristina Fillat at the Centre for Genomic Regulation (CRG) in Barcelona. Wanting to move into more basic research, Meri trained as a postdoc with Hans Clevers at the Hubrecht Institute in the Netherlands. In her postdoctoral research, she successfully established a liver organoid culture that earned her the National Centre for Replacement, Refinement and Reduction of Animals in Research (NC3Rs) prize in 2013...
August 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27494556/who-is-in-the-driver-s-seat-tracing-cancer-genes-using-crispr-barcoding
#14
Jarno Drost, Hans Clevers
Intratumor heterogeneity is thought to be the driving force of tumor evolution and therapy resistance. Yet tools to study these processes are limited. In this issue, Guernet et al. (2016) devised clustered regularly interspaced short palindromic repeats (CRISPR)-barcoding to functionally annotate specific mutations and study clonal evolution in heterogeneous cell populations.
August 4, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27493992/analysis-of-neural-crest-derived-clones-reveals-novel-aspects-of-facial-development
#15
Marketa Kaucka, Evgeny Ivashkin, Daniel Gyllborg, Tomas Zikmund, Marketa Tesarova, Jozef Kaiser, Meng Xie, Julian Petersen, Vassilis Pachnis, Silvia K Nicolis, Tian Yu, Paul Sharpe, Ernest Arenas, Hjalmar Brismar, Hans Blom, Hans Clevers, Ueli Suter, Andrei S Chagin, Kaj Fried, Andreas Hellander, Igor Adameyko
Cranial neural crest cells populate the future facial region and produce ectomesenchyme-derived tissues, such as cartilage, bone, dermis, smooth muscle, adipocytes, and many others. However, the contribution of individual neural crest cells to certain facial locations and the general spatial clonal organization of the ectomesenchyme have not been determined. We investigated how neural crest cells give rise to clonally organized ectomesenchyme and how this early ectomesenchyme behaves during the developmental processes that shape the face...
August 2016: Science Advances
https://www.readbyqxmd.com/read/27345837/de-novo-prediction-of-stem-cell-identity-using-single-cell-transcriptome-data
#16
Dominic Grün, Mauro J Muraro, Jean-Charles Boisset, Kay Wiebrands, Anna Lyubimova, Gitanjali Dharmadhikari, Maaike van den Born, Johan van Es, Erik Jansen, Hans Clevers, Eelco J P de Koning, Alexander van Oudenaarden
Adult mitotic tissues like the intestine, skin, and blood undergo constant turnover throughout the life of an organism. Knowing the identity of the stem cell is crucial to understanding tissue homeostasis and its aberrations upon disease. Here we present a computational method for the derivation of a lineage tree from single-cell transcriptome data. By exploiting the tree topology and the transcriptome composition, we establish StemID, an algorithm for identifying stem cells among all detectable cell types within a population...
August 4, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27334259/characterizing-responses-to-cftr-modulating-drugs-using-rectal-organoids-derived-from-subjects-with-cystic-fibrosis
#17
Johanna F Dekkers, Gitte Berkers, Evelien Kruisselbrink, Annelotte Vonk, Hugo R de Jonge, Hettie M Janssens, Inez Bronsveld, Eduard A van de Graaf, Edward E S Nieuwenhuis, Roderick H J Houwen, Frank P Vleggaar, Johanna C Escher, Yolanda B de Rijke, Christof J Majoor, Harry G M Heijerman, Karin M de Winter-de Groot, Hans Clevers, Cornelis K van der Ent, Jeffrey M Beekman
Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations...
June 22, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27329244/rnf43-germline-and-somatic-mutation-in-serrated-neoplasia-pathway-and-its-association-with-braf-mutation
#18
Helen H N Yan, Jeffrey C W Lai, Siu Lun Ho, Wai Keung Leung, Wai Lun Law, Janet F Y Lee, Anthony K W Chan, Wai Yin Tsui, Annie S Y Chan, Bernard C H Lee, Sarah S K Yue, Alice H Y Man, Hans Clevers, Siu Tsan Yuen, Suet Yi Leung
OBJECTIVE: Serrated polyps (hyperplastic polyps, sessile or traditional serrated adenomas), which can arise in a sporadic or polyposis setting, predispose to colorectal cancer (CRC), especially those with microsatellite instability (MSI) due to MLH1 promoter methylation (MLH1(me+)). We investigate genetic alterations in the serrated polyposis pathway. DESIGN: We used a combination of exome sequencing and target gene Sanger sequencing to study serrated polyposis families, sporadic serrated polyps and CRCs, with validation by analysis of The Cancer Genome Atlas (TCGA) cohort, followed by organoid-based functional studies...
June 21, 2016: Gut
https://www.readbyqxmd.com/read/27315476/modeling-development-and-disease-with-organoids
#19
REVIEW
Hans Clevers
Recent advances in 3D culture technology allow embryonic and adult mammalian stem cells to exhibit their remarkable self-organizing properties, and the resulting organoids reflect key structural and functional properties of organs such as kidney, lung, gut, brain and retina. Organoid technology can therefore be used to model human organ development and various human pathologies 'in a dish." Additionally, patient-derived organoids hold promise to predict drug response in a personalized fashion. Organoids open up new avenues for regenerative medicine and, in combination with editing technology, for gene therapy...
June 16, 2016: Cell
https://www.readbyqxmd.com/read/27308531/model-organoids-provide-new-research-opportunities-for-ductal-pancreatic-cancer
#20
Sylvia F Boj, Chang-Il Hwang, Lindsey A Baker, Dannielle D Engle, David A Tuveson, Hans Clevers
We recently established organoid models from normal and neoplastic murine and human pancreas tissues. These organoids exhibit ductal- and disease stage-specific characteristics and, after orthotopic transplantation, recapitulate the full spectrum of tumor progression. Pancreatic organoid technology provides a novel platform for the study of tumor biology and the discovery of potential biomarkers, therapeutics, and personalized medicine strategies.
January 2016: Molecular & Cellular Oncology
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