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Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors
Koo, Bon-Kyoung,Spit, Maureen,Jordens, Ingrid,Low, Teck Y.,Stange, Daniel E.,van de Wetering, Marc,van Es, Johan H.,Mohammed, Shabaz,Heck, Albert J. R.,Maurice, Madelon M.,Clevers, Hans Nature Publishing Group, a division of Macmillan P 2012 Nature Vol.488 No.7413
LGR5<SUP>+</SUP> stem cells reside at crypt bottoms, intermingled with Paneth cells that provide Wnt, Notch and epidermal growth factor signals. Here we find that the related RNF43 and ZNRF3 transmembrane E3 ubiquitin ligases are uniquely expressed in LGR5<SUP>+</SUP> stem cells. Simultaneous deletion of the two genes encoding these proteins in the intestinal epithelium of mice induces rapidly growing adenomas containing high numbers of Paneth and LGR5<SUP>+</SUP> stem cells. In vitro, growth of organoids derived from these adenomas is arrested when Wnt secretion is inhibited, indicating a dependence of the adenoma stem cells on Wnt produced by adenoma Paneth cells. In the HEK293T human cancer cell line, expression of RNF43 blocks Wnt responses and targets surface-expressed frizzled receptors to lysosomes. In the RNF43-mutant colorectal cancer cell line HCT116, reconstitution of RNF43 expression removes its response to exogenous Wnt. We conclude that RNF43 and ZNRF3 reduce Wnt signals by selectively ubiquitinating frizzled receptors, thereby targeting these Wnt receptors for degradation.
Stange, Daniel E.,Koo, B.K.,Huch, M.,Sibbel, G.,Basak, O.,Lyubimova, A.,Kujala, P.,Bartfeld, S.,Koster, J.,Geahlen, Jessica H.,Peters, Peter J.,van Es, Johan H.,van de Wetering, M.,Mills, Jason C.,Cle Cell Press ; MIT Press 2013 Cell Vol.155 No.2
Proliferation of the self-renewing epithelium of the gastric corpus occurs almost exclusively in the isthmus of the glands, from where cells migrate bidirectionally toward pit and base. The isthmus is therefore generally viewed as the stem cell zone. We find that the stem cell marker Troy is expressed at the gland base by a small subpopulation of fully differentiated chief cells. By lineage tracing with a Troy-eGFP-ires-CreERT2 allele, single marked chief cells are shown to generate entirely labeled gastric units over periods of months. This phenomenon accelerates upon tissue damage. Troy<SUP>+</SUP> chief cells can be cultured to generate long-lived gastric organoids. Troy marks a specific subset of chief cells that display plasticity in that they are capable of replenishing entire gastric units, essentially serving as quiescent ''reserve'' stem cells. These observations challenge the notion that stem cell hierarchies represent a ''one-way street.''
Gastrointestinal cancer organoids—applications in basic and translational cancer research
Seidlitz Therese,Stange Daniel E. 생화학분자생물학회 2021 Experimental and molecular medicine Vol.53 No.-
Cancer is a major health problem and a leading cause of death worldwide. Early cancer detection and continuous changes in treatment strategies have improved overall patient survival. The recent development of targeted drugs offers new opportunities for personalized cancer treatment. Nevertheless, individualized treatment is accompanied by the need for biomarkers predicting the response of a patient to a certain drug. One of the most promising breakthroughs in recent years that might help to overcome this problem is the organoid technology. Organoid cultures exhibit self-renewal capacity, self-organization, and long-term proliferation, while recapitulating many aspects of their primary tissue. Generated patient-derived organoid (PDO) libraries constitute “living” biobanks, allowing the in-depth analysis of tissue function, development, tumor initiation, and cancer pathobiology. Organoids can be derived from all gastrointestinal tissues, including esophageal, gastric, liver, pancreatic, small intestinal and colorectal tissues, and cancers of these tissues. PDOs are amenable to various techniques, including sequencing analyses, drug screening, targeted therapy testing, tumor microenvironment studies, and genetic engineering capabilities. In this review, we discuss the different applications of gastrointestinal organoids in basic cancer biology and clinical translation.
Notch1 counteracts WNT/β-catenin signaling through chromatin modification in colorectal cancer.
Kim, Hyun-A,Koo, Bon-Kyoung,Cho, Ji-Hoon,Kim, Yoon-Young,Seong, Jinwoo,Chang, Hee Jin,Oh, Young Min,Stange, Daniel E,Park, Jae-Gahb,Hwang, Daehee,Kong, Young-Yun American Society for Clinical Investigation 2012 The Journal of clinical investigation Vol.122 No.9
<P>Crosstalk between the Notch and wingless-type MMTV integration site (WNT) signaling pathways has been investigated for many developmental processes. However, this negative correlation between Notch and WNT/β-catenin signaling activity has been studied primarily in normal developmental and physiological processes in which negative feedback loops for both signaling pathways are intact. We found that Notch1 signaling retained the capability of suppressing the expression of WNT target genes in colorectal cancers even when β-catenin destruction by the adenomatous polyposis coli (APC) complex was disabled. Activation of Notch1 converted high-grade adenoma into low-grade adenoma in an Apcmin mouse colon cancer model and suppressed the expression of WNT target genes in human colorectal cancer cells through epigenetic modification recruiting histone methyltransferase SET domain bifurcated 1 (SETDB1). Extensive microarray analysis of human colorectal cancers also showed a negative correlation between the Notch1 target gene, Notch-regulated ankyrin repeat protein 1 (NRARP), and WNT target genes. Notch is known to be a strong promoter of tumor initiation, but here we uncovered an unexpected suppressive role of Notch1 on WNT/β-catenin target genes involved in colorectal cancer.</P>