The β-Catenin/TCF-4 Complex Imposes a Crypt Progenitor Phenotype on Colorectal Cancer Cells

Wetering, Marc van de; Sancho, Elena; Verweij, Cornelis L.; Lau, Wim de; Oving, Irma M.; Hurlstone, Adam; Horn, Karin van der; Batlle, Eduard; Coudreuse, Damien; Haramis, Anna Pavlina G; Tjon-Pon-Fong, Menno; Moerer, Petra; Born, Marise Ph.; Soete, Gwen; Pals, Steven T.; Eilers, Martin; Medema, René H.; Clevers, Hans

doi:10.1016/s0092-8674(02)01014-0

Cited by 1,866 publications

(1,656 citation statements)

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“…Both mutations have previously been characterized as highly activating. 20 Transcription mediated by FOXO3 or LEF/TCF, which are associated with PI3K/AKT and Wnt/β-catenin signal transduction, respectively, 7,21 was not altered by either mutation.…”

Section: Resultsmentioning

confidence: 92%

“…In line, loss of intestinal Wnt/β-catenin signals by genetic ablation of the transcription factor TCF4 results in loss of the stem cell compartment and ultimately in loss of the intestinal epithelium in the mouse. 7,8 In contrast, activation of β-catenin is sufficient to modulate intestinal cellular hierarchies toward adenomatous stem cell fates. 9 Sessile serrated adenomas (SSAs) constitute a distinct class of premalignant tumors in the intestine, which are characterized by a saw-toothed and tufted tissue morphology, as well as by unique transcriptional, mutational and epigenetic patterns.…”

Section: Introductionmentioning

confidence: 99%

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Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

et al. 2014

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Colon cancer cells frequently carry mutations that activate the β-catenin and mitogen-activated protein kinase (MAPK) signaling cascades. Yet how oncogenic alterations interact to control cellular hierarchies during tumor initiation and progression is largely unknown. We found that oncogenic BRAF modulates gene expression associated with cell differentiation in colon cancer cells. We therefore engineered a mouse with an inducible oncogenic BRAF transgene, and analyzed BRAF effects on cellular hierarchies in the intestinal epithelium in vivo and in primary organotypic culture. We demonstrate that transgenic expression of oncogenic BRAF in the mouse strongly activated MAPK signal transduction, resulted in the rapid development of generalized serrated dysplasia, but unexpectedly also induced depletion of the intestinal stem cell (ISC) pool. Histological and gene expression analyses indicate that ISCs collectively converted to short-lived progenitor cells after BRAF activation. As Wnt/β-catenin signals encourage ISC identity, we asked whether β-catenin activity could counteract oncogenic BRAF. Indeed, we found that intestinal organoids could be partially protected from deleterious oncogenic BRAF effects by Wnt3a or by small-molecule inhibition of GSK3β. Similarly, transgenic expression of stabilized β-catenin in addition to oncogenic BRAF partially prevented loss of stem cells in the mouse intestine. We also used BRAF V637E knock-in mice to follow changes in the stem cell pool during serrated tumor progression and found ISC marker expression reduced in serrated hyperplasia forming after BRAF activation, but intensified in progressive dysplastic foci characterized by additional mutations that activate the Wnt/β-catenin pathway. Our study suggests that oncogenic alterations activating the MAPK and Wnt/β-catenin pathways must be consecutively and coordinately selected to assure stem cell maintenance during colon cancer initiation and progression. Notably, loss of stem cell identity upon induction of BRAF/MAPK activity may represent a novel fail-safe mechanism protecting intestinal tissue from oncogene activation.

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Section: Resultsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

et al. 2014

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“…b-Catenin is also found to immunoprecipitate with the APC tumour suppressor protein (Su et al, 1993;Hulsken et al, 1994;Shibata et al, 1994), and has been recently identified as an oncogene (Kim et al, 2002;Minamoto et al, 2002;Kielhorn et al, 2003;Schneider et al, 2003). It is also central to cell signalling, as upon dissociation from E-cadherin, it transits to the nucleus to alter transcriptional profiles (Mason et al, 2002;van de Wetering et al, 2002). A reduction in b-catenin expression decreases the stability of the adhesion complex and likely results in impairment in E-cadherin function (Willert and Nusse, 1998;Lowy et al, 2002;Mason et al, 2002).…”

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confidence: 99%

Luteinising hormone-releasing hormone analogue reverses the cell adhesion profile of EGFR overexpressing DU-145 human prostate carcinoma subline

2005

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Cetrorelix, a luteinising hormone-releasing hormone (LHRH) analogue, has been shown to limit growth of the human androgenindependent prostate cell line DU-145, although other inhibitory actions may also be affected. Both growth and invasion of DU-145 cells are linked to autocrine epidermal growth factor receptor (EGFR) signalling. Invasiveness requires not only cells to migrate to conduits, but also reduced adhesiveness between tumour cells to enable separation from the tumour mass. Thus, we investigated whether Cetrorelix alters the DU-145 cell -cell adhesion and if this occurs via altered EGFR signalling. Pharmacologic levels of Cetrorelix limited the invasiveness of a highly invasive DU-145 subline overexpressing full-length EGFR (DU-145 WT). Extended exposure of the cells to Cetrorelix resulted in increased levels of the cell -cell adhesion complex molecules E-cadherin, a-and bcatenin, and p120. Puromycin blocked the increases in E-cadherin and b-catenin levels, suggesting that de novo protein synthesis is required. The Cetrorelix effect appears to occur via transmodulation of EGFR by a protein kinase C (PKC)-dependent mechanism, as there were no changes in DU-145 cells expressing EGFR engineered to negate the PKC transattenuation site (DU-145 A654); downregulation of EGFR signalling produced a similar upregulation in adhesion complex proteins, further suggesting a role for autocrine signalling. Cetrorelix increased the cell -cell adhesiveness of DU-145 WT cells to an extent similar to that seen when autocrine EGFR signalling is blocked; as expected, DU-145 A654 cell -cell adhesion also was unaffected by Cetrorelix. The increased adhesiveness is expected as the adhesion complex molecules moved to the cells' periphery. These data offer direct insight into the possible crosstalk pathways between the LHRH and EGFR receptor signalling. The ability of Cetrorelix to downregulate EGFR signalling and subsequently reverse the antiadhesiveness found in metastatic prostate cancer highlights a novel potential target for therapeutic strategies.

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“…The TCF4 variant [(designated as dominant negative TCF4 (dnTCF4)] binds the regulatory regions in Wnt‐responsive genes. Nevertheless, due to the disruption of the β‐catenin interaction domain (Korinek et al ., 1997; van de Wetering et al ., 2002), it cannot associate with β‐catenin and acts as a nuclear blocker of canonical Wnt signaling. Additionally, a sequence encoding a tandem dimer (td) of red fluorescent protein Tomato flanked (i.e.…”

Section: Introductionmentioning

confidence: 99%

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

Janečková

Fafílek

Krausová

et al. 2016

Genesis

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SummaryThe Wnt pathway plays a crucial role in self‐renewal and differentiation of cells in the adult gut. In the present study, we revealed the functional consequences of inhibition of canonical Wnt signaling in the intestinal epithelium. The study was based on generation of a novel transgenic mouse strain enabling inducible expression of an N‐terminally truncated variant of nuclear Wnt effector T cell factor 4 (TCF4). The TCF4 variant acting as a dominant negative (dn) version of wild‐type (wt) TCF4 protein decreased transcription of β‐catenin‐TCF4‐responsive genes. Interestingly, suppression of Wnt/β‐catenin signaling affected asymmetric division of intestinal stem cells (ISCs) rather than proliferation. ISCs expressing the transgene underwent several rounds of division but lost their clonogenic potential and migrated out of the crypt. Expression profiling of crypt cells revealed that besides ISC‐specific markers, the dnTCF4 production downregulated expression levels of epithelial genes produced in other crypt cells including markers of Paneth cells. Additionally, in Apc conditional knockout mice, dnTCF activation efficiently suppressed growth of Apc‐deficient tumors. In summary, the generated mouse strain represents a convenient tool to study cell‐autonomous inhibition of β‐catenin‐Tcf‐mediated transcription. genesis 54:101–114, 2016. © 2016 The Authors genesis Published by Wiley Periodicals, Inc.

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The β-Catenin/TCF-4 Complex Imposes a Crypt Progenitor Phenotype on Colorectal Cancer Cells

Cited by 1,866 publications

References 41 publications

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

Luteinising hormone-releasing hormone analogue reverses the cell adhesion profile of EGFR overexpressing DU-145 human prostate carcinoma subline

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

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