82 results found
Stoletov K, Sanchez S, Gorrono I, et al., 2023, Intravital imaging of Wnt/β-catenin and ATF2-dependent signalling pathways during tumour cell invasion and metastasis, Journal of Cell Science, Vol: 136, ISSN: 0021-9533
Wnt signalling has been implicated as a driver of tumour cell metastasis, but less is known about which branches of Wnt signalling are involved and when they act in the metastatic cascade. Here, using a unique intravital imaging platform and fluorescent reporters, we visualised β-catenin/TCF-dependent and ATF2-dependent signalling activities during human cancer cell invasion, intravasation and metastatic lesion formation in the chick embryo host. We found that cancer cells readily shifted between states of low and high canonical Wnt activity. Cancer cells that displayed low Wnt canonical activity showed higher invasion and intravasation potential in primary tumours and in metastatic lesions. In contrast, cancer cells showing low ATF2-dependent activity were significantly less invasive both at the front of primary tumours and in metastatic lesions. Simultaneous visualisation of both these reporters using a double-reporter cell line confirmed their complementary activities in primary tumours and metastatic lesions. These findings might inform the development of therapies that target different branches of Wnt signalling at specific stages of metastasis.
Al Shareef Z, Ershaid MNA, Mudhafar R, et al., 2022, Dickkopf-3: an update on a potential regulator of the tumor microenvironment, Cancers, Vol: 14, Pages: 1-16, ISSN: 2072-6694
Dickkopf-3 (Dkk-3) is a member of the Dickkopf family protein of secreted Wingless-related integration site (Wnt) antagonists that appears to modulate regulators of the host microenvironment. In contrast to the clear anti-tumorigenic effects of Dkk-3-based gene therapies, the role of endogenous Dkk-3 in cancer is context-dependent, with elevated expression associated with tumor promotion and suppression in different settings. The receptors and effectors that mediate the diverse effects of Dkk-3 have not been characterized in detail, contributing to an ongoing mystery of its mechanism of action. This review compares the various functions of Dkk-3 in the tumor microenvironment, where Dkk-3 has been found to be expressed by subpopulations of fibroblasts, endothelial, and immune cells, in addition to epithelial cells. We also discuss how the activation or inhibition of Dkk-3, depending on tumor type and context, might be used to treat different types of cancers.
Lewis A, Sánchez S, Berti G, et al., 2022, Small-molecule Wnt inhibitors are a potential novel therapy for intestinal fibrosis in Crohns disease, Clinical Science, Vol: 136, Pages: 1405-1423, ISSN: 0143-5221
Intestinal fibrosis and stricture formation is an aggressive complication of Crohns disease (CD), linked to increased morbidity and costs. The present study investigates the contribution of Wingless-Int-1 (Wnt) signalling to intestinal fibrogenesis, considers potential cross-talk between Wnt and transforming growth factor β1 (TGFβ) signalling pathways, and assesses the therapeutic potential of small-molecule Wnt inhibitors.β-catenin expression was explored by immunohistochemistry (IHC) in formalin-fixed paraffin embedded (FFPE) tissue from patient-matched nonstrictured (NSCD) and strictured (SCD) intestine (n=6 pairs). Functional interactions between Wnt activation, TGFβ signalling, and type I collagen (Collagen-I) expression were explored in CCD-18Co cells and primary CD myofibroblast cultures established from surgical resection specimens (n=16) using small-molecule Wnt inhibitors and molecular techniques, including siRNA-mediated gene knockdown, immunofluorescence (IF), Wnt gene expression arrays, and western blotting. Fibrotic SCD tissue was marked by an increase in β-catenin-positive cells. In vitro, activation of Wnt-β-catenin signalling increased Collagen-I expression in CCD-18Co cells. Conversely, ICG-001, an inhibitor of β-catenin signalling, reduced Collagen-I expression in cell lines and primary CD myofibroblasts. TGFβ increased β-catenin protein levels but did not activate canonical Wnt signalling. Rather, TGFβ up-regulated WNT5B, a noncanonical Wnt ligand, and the Wnt receptor FZD8, which contributed directly to the up-regulation of Collagen-I through a β-catenin-independent mechanism. Treatment of CCD-18Co fibroblasts and patient-derived myofibroblasts with the FZD8 inhibitor 3235-0367 reduced extracellular matrix (ECM) expression. Our data highlight small-molecule Wnt inhibitors of both canonical and noncanonical Wnt signalling, as potential antifibrotic drugs to treat SCD intestinal fibrosis. They
Spethmann T, Böckelmann LC, Labitzky V, et al., 2021, Opposing prognostic relevance of junction plakoglobin in distinct prostate cancer patient subsets, Molecular Oncology, Vol: 15, Pages: 1956-1969, ISSN: 1574-7891
Both oncogenic and tumor suppressor functions have been described for junction plakoglobin (JUP), also known as γ-catenin. To clarify the role of JUP in prostate cancer, JUP protein expression was immunohistochemically detected in a tissue microarray containing 11 267 individual prostatectomy specimens. Considering all patients, high JUP expression was associated with adverse tumor stage (P = 0.0002), high Gleason grade (P < 0.0001), and lymph node metastases (P = 0.011). These associations were driven mainly by the subset without TMPRSS2:ERG fusion, in which high JUP expression was an independent predictor of poor prognosis (multivariate analyses, P = 0.0054) and early biochemical recurrence (P = 0.0003). High JUP expression was further linked to strong androgen receptor expression (P < 0.0001), high cell proliferation, and PTEN and FOXP1 deletion (P < 0.0001). In the ERG-negative subset, high JUP expression was additionally linked to MAP3K7 (P = 0.0007) and CHD1 deletion (P = 0.0021). Contrasting the overall prognostic effect of JUP, low JUP expression indicated poor prognosis in the fraction of CHD1-deleted patients (P = 0.039). In this subset, the association of high JUP and high cell proliferation was specifically absent. In conclusion, the controversial biological roles of JUP are reflected by antagonistic prognostic effects in distinct prostate cancer patient subsets.
Sunters A, Armstrong VJ, Zaman G, et al., 2021, Mechano-transduction in Osteoblastic Cells Involves Strain-regulated Estrogen Receptor alpha-mediated Control of Insulin-like Growth Factor (IGF) I Receptor Sensitivity to Ambient IGF, Leading to Phosphatidylinositol 3-Kinase/AKT-dependent Wnt/LRP5 Receptor-independent Activation of beta-Catenin Signaling, Journal of Biological Chemistry, Vol: 285, Pages: 8743-8758, ISSN: 0021-9258
The capacity of bones to adjust their mass and architecture to withstand the loads of everyday activity derives from the ability of their resident cells to respond appropriately to the strains engendered. To elucidate the mechanisms of strain responsiveness in bone cells, we investigated in vitro the responses of primary mouse osteoblasts and UMR-106 osteoblast-like cells to a single period of dynamic strain. This stimulates a cascade of events, including activation of insulin-like growth factor I receptor (IGF-IR), phosphatidylinositol 3-kinase-mediated phosphorylation of AKT, inhibition of GSK-3β, increased activation of β-catenin, and associated lymphoid-enhancing factor/T cell factor-mediated transcription. Initiation of this pathway does not involve the Wnt/LRP5/Frizzled receptor and does not culminate in increased IGF transcription. The effect of strain on IGF-IR is mimicked by exogenous des-(1–3)IGF-I and is blocked by the IGF-IR inhibitor H1356. Inhibition of strain-related prostanoid and nitric oxide production inhibits strain-related (and basal) AKT activity, but their separate ectopic administration does not mimic it. Strain-related IGF-IR activation of AKT requires estrogen receptor α (ERα) with which IGF-1R physically associates. The ER blocker ICI 182,780 increases the concentration of des-(1–3)IGF-I necessary to activate this cascade, whereas estrogen inhibits both basal AKT activity and its activation by des-(1–3)IGF-I. These data suggest an initial cascade of strain-related events in osteoblasts in which strain activates IGF-IR, in association with ERα, so initiating phosphatidylinositol 3-kinase/AKT-dependent activation of β-catenin and altered lymphoid-enhancing factor/T cell factor transcription. This cascade requires prostanoid/nitric oxide production and is independent of Wnt/LRP5.
Gorroño-Etxebarria I, Aguirre U, Sanchez S, et al., 2019, Wnt-11 as a potential prognostic biomarker and therapeutic target in colorectal cancer, Cancers, Vol: 11, ISSN: 2072-6694
The expression of the secreted factor Wnt-11 is elevated in several types of cancer, includingcolorectal cancer, where it promotes cancer cell migration and invasion. Analysis of colorectalcancer gene expression databases associated WNT11 mRNA expression with increased likelihood ofmetastasis in a subset of patients. WNT11 expression was correlated with the expression of the Wntreceptors FZD6, RYK, and PTK7, and the combined expression of WNT11, FZD6 and RYK or PTK7was associated with an increased risk of 5-year mortality rates. Immunohistochemical analysis ofWnt-11 in a cohort of 357 colorectal cancer patients found significantly higher Wnt-11 levels in tumors,compared with benign tissue. Elevated Wnt-11 levels occurred more frequently in rectal tumors thanin colonic tumors and in tumors from women than men. In univariate analysis, increased Wnt-11expression was also associated with tumor invasion and increased 5-year mortality. High Wnt-11levels were not associated with high levels of nuclear β-catenin, suggesting Wnt-11 is not simplyan indicator for activation of β-catenin-dependent signaling. Expression of Wnt-11 in colorectalcancer cell lines expressing low endogenous Wnt-11 inhibited β-catenin/Tcf activity and increasedATF2-dependent transcriptional activity. WNT11 gene silencing and antibody-mediated inhibitionof Wnt-11 in colorectal cancer cell lines expressing high Wnt-11 reduced their capacity for invasion.Together, these observations suggest that Wnt-11 could be a potential target for the treatment ofpatients with invasive colorectal cancer.
Ormaza G, Rodríguez JA, de Opakua AI, et al., 2019, The tumor suppressor ING5 is a dimeric, bivalent recognition molecule of the histone H3K4me3 mark, Journal of Molecular Biology, Vol: 431, Pages: 2298-2319, ISSN: 0022-2836
The INhibitor of Growth (ING) family of tumor suppressors regulates the transcriptional state of chromatin by recruiting remodeling complexes to sites with histone H3 trimethylated at lysine 4 (H3K4me3). This modification is recognized by the plant homeodomain (PHD) present at the C-terminus of the five ING proteins. ING5 facilitates histone H3 acetylation by the HBO1 complex, and also H4 acetylation by the MOZ/MORF complex. We show that ING5 forms homodimers through its N-terminal domain, which folds independently into an elongated coiled-coil structure. The central region of ING5, which contains the nuclear localization sequence, is flexible and disordered, but it binds dsDNA with micromolar affinity. NMR analysis of the full-length protein reveals that the two PHD fingers of the dimer are chemically equivalent and independent of the rest of the molecule, and they bind H3K4me3 in the same way as the isolated PHD. We have observed that ING5 can form heterodimers with the highly homologous ING4, and that two of three primary tumor-associated mutants in the N-terminal domain strongly destabilize the coiled-coil structure. They also affect cell proliferation and cell cycle phase distribution, suggesting a driver role in cancer progression.
Domenici G, Aurrekoetxea-Rodríguez I, Simões BM, et al., 2019, A Sox2–Sox9 signalling axis maintains human breast luminalprogenitor and breast cancer stem cells, Oncogene, Vol: 38, Pages: 3151-3169, ISSN: 0950-9232
Increased cancer stem cell content during development of resistance to tamoxifen in breast cancer is driven by multiple signals, including Sox2-dependent activation of Wnt signalling. Here, we show that Sox2 increases and estrogen reduces the expression of the transcription factor Sox9. Gain and loss of function assays indicate that Sox9 is implicated in the maintenance of human breast luminal progenitor cells. CRISPR/Cas knockout of Sox9 reduces growth of tamoxifen-resistant breast tumours in vivo. Mechanistically, Sox9 acts downstream of Sox2 to control luminal progenitor cell content and is required for expression of the cancer stem cell marker ALDH1A3 and Wnt signalling activity. Sox9 is elevated in breast cancer patients after endocrine therapy failure. This new regulatory axis highlights the relevance of SOX family transcription factors as potential therapeutic targets in breast cancer.
Ramos A, Rodríguez-Seoane C, Rosa I, et al., 2019, Proteomic studies reveal disrupted in schizophrenia 1 as a player in both neurodevelopment and synaptic function, International Journal of Molecular Sciences, Vol: 20, ISSN: 1422-0067
A balanced chromosomal translocation disrupting DISC1 (Disrupted in Schizophrenia 1) gene has been linked to psychiatric diseases, such as major depression, bipolar disorder and schizophrenia. Since the discovery of this translocation, many studies have focused on understating the role of the truncated isoform of DISC1, hypothesizing that the gain of function of this protein could be behind the neurobiology of mental conditions, but not so many studies have focused in the mechanisms impaired due to its loss of function. For that reason, we performed an analysis on the cellular proteome of primary neurons in which DISC1 was knocked down with the goal of identifying relevant pathways directly affected by DISC1 loss of function. Using an unbiased proteomic approach, we found that the expression of 31 proteins related to neurodevelopment (e.g., CRMP-2, stathmin) and synaptic function (e.g., MUNC-18, NCS-1) is altered by DISC1 in primary mouse neurons. Hence, this study reinforces the idea that DISC1 is a unifying regulator of both neurodevelopment and synaptic function, thereby providing a link between these two key anatomical and cellular circuitries.
Mazo C, Orue-Etxebarria E, Zabalza I, et al., 2018, In silico approach for immunohistochemical evaluation of a cytoplasmic marker in breast cancer, Cancers, Vol: 10, ISSN: 2072-6694
Breast cancer is the most frequently diagnosed cancer in women and the second most common cancer overall, with nearly 1.7 million new cases worldwide every year. Breast cancer patients need accurate tools for early diagnosis and to improve treatment. Biomarkers are increasingly used to describe and evaluate tumours for prognosis, to facilitate and predict response to therapy and to evaluate residual tumor, post-treatment. Here, we evaluate different methods to separate Diaminobenzidine (DAB) from Hematoxylin and Eosin (H&E) staining for Wnt-1, a potential cytoplasmic breast cancer biomarker. A method comprising clustering and Color deconvolution allowed us to recognize and quantify Wnt-1 levels accurately at pixel levels. Experimental validation was conducted using a set of 12,288 blocks of m × n pixels without overlap, extracted from a Tissue Microarray (TMA) composed of 192 tissue cores. Intraclass Correlations (ICC) among evaluators of the data of 0.634 , 0.791 , 0.551 and 0.63 for each Allred class and an average ICC of 0.752 among evaluators and automatic classification were obtained. Furthermore, this method received an average rating of 4.26 out of 5 in the Wnt-1 segmentation process from the evaluators.
Al-Shareef Z, Kardooni H, Murillo-Garzon V, et al., 2018, Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1, Oncogene, Vol: 37, Pages: 5305-5324, ISSN: 0950-9232
Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromalmicroenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, isdownregulated in prostate cancer and upregulated in the stroma in benign prostatichyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencingin WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cellconditionedmedia inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI)in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostatecancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated withincreased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrixprotein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelialcell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancercell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors wasassociated with increased relapse-free survival. These observations are consistent with amodel in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBIand ECM-1, which have tumor-promoting and tumor-protective roles, respectively.Determining how the balance between the opposing roles of extracellular factors influencesprostate carcinogenesis will be key to developing therapies that target the tumormicroenvironment.
Kardooni H, Gonzalez-Gualda E, Stylianakis E, et al., 2018, CRISPR-mediated reactivation of DKK3 expression attenuates TGF-beta signaling in prostate cancer, Cancers, Vol: 10, ISSN: 2072-6694
The DKK3 gene encodes a secreted protein, Dkk-3, that inhibits prostate tumor growth and metastasis. DKK3 is downregulated by promoter methylation in many types of cancer, including prostate cancer. Gene silencing studies have shown that Dkk-3 maintains normal prostate epithelial cell homeostasis by limiting TGF-β/Smad signaling. While ectopic expression of Dkk-3 leads to prostate cancer cell apoptosis, it is unclear if Dkk-3 has a physiological role in cancer cells. Here, we show that treatment of PC3 prostate cancer cells with the DNA methyltransferase (DNMT) inhibitor decitabine demethylates the DKK3 promoter, induces DKK3 expression, and inhibits TGF-β/Smad-dependent transcriptional activity. Direct induction of DKK3 expression using CRISPR-dCas9-VPR also inhibited TGF-β/Smad-dependent transcription and attenuated PC3 cell migration and proliferation. These effects were not observed in C4-2B cells, which do not respond to TGF-β. TGF-β signals can regulate gene expression directly via SMAD proteins and indirectly by increasing DNMT expression, leading to promoter methylation. Analysis of genes downregulated by promoter methylation and predicted to be regulated by TGF-β found that DKK3 induction increased expression of PTGS2, which encodes cyclooxygenase-2. Together, these observations provide support for using CRISPR-mediated induction of DKK3 as a potential therapeutic approach for prostate cancer and highlight complexities in Dkk-3 regulation of TGF-β signaling.
Murillo-Garzón V, Gorroño-Etxebarria I, Åkerfelt M, et al., 2018, Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer, Nature Communications, Vol: 9, ISSN: 2041-1723
Wnt-11 promotes cancer cell migration and invasion independently of β-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD8 is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-β signals to promote EMT. FZD8 mRNA is upregulated in multiple prostate cancer datasets and in metastatic cancer cell lines in vitro and in vivo. Analysis of patient samples reveals increased levels of FZD8 in cancer, correlating with Wnt-11. FZD8 co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD8 silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-β/Smad-dependent signaling. Mechanistically, FZD8 forms a TGF-β-regulated complex with TGF-β receptors that is mediated by the extracellular domains of FZD8 and TGFBR1. Targeting FZD8 may therefore inhibit aberrant activation of both Wnt and TGF-β signals in prostate cancer.
Murillo-Garzón V, Kypta R, 2017, WNT signalling in prostate cancer, Nature Reviews Urology, Vol: 14, Pages: 683-696, ISSN: 1743-4270
Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer.
Bengoa-Vergniory N, Kypta R, 2016, The stem cell cocktail: neural reprogramming just got easier, Stem Cell Investigation, Vol: 3, Pages: 55-55, ISSN: 2313-0792
Bengoa-Vergniory N, Gorrono-Etxebarria I, Lopez- Sanchez I, et al., 2016, Identification of non-canonical Wnt receptors required for Wnt-3a-induced early differentiation of human neural stem cells, Molecular Neurobiology, Vol: 54, Pages: 6213-6224, ISSN: 1559-1182
Wnt proteins preferentially activate either β-catenin-dependent or β-cateninindependentsignals, but the activity of a particular Wnt also depends on cellularcontext and receptor availability. We previously reported that Wnt-3a inducesneural differentiation of human embryonic stem cell-derived neural stem cells(NSCs) in a β-catenin-independent manner by activating a signal involving JNK andthe AP-1 family member ATF-2. Here, we report the results of a gene silencingapproach to identify the Wnt receptors that mediate this response to Wnt-3a.Silencing of ROR2 increased neuronal differentiation, as measured by expressionof the genes DCX, NEUROD1 and NGN1, suggesting ROR2 signals normally preventdifferentiation. Silencing of the other Wnt receptors singly did not affect Wnt-3ainducedneuronal differentiation. However, pair-wise silencing of ROR1 and FZD4or FZD5 and of LRP6 and FZD4 or FZD5 inhibited neuronal differentiation, asdetected by reductions in the expression of neuronal genes andimmunocytochemical detection of DCX and NEUROD1 and DCX. Ectopic expressionof these receptors in HEK 293 cells increased ATF2-dependent transcription. Inaddition, ROR1 co-immunoprecipitated with FZD4 and LRP6 in transfected HEK293 cells and colocalized with FZD4 and with LRP6 at the cell surface oftransfected L cells. Wnt-3a did not appear to affect these interactions but did alterthe interactions between LRP6 and FZD4/5. Together, these observations highlightroles for ROR1, LRP6, FZD4 and FZD5 in neural stem cell differentiation andprovide support for a model in which dynamic interactions among these receptorsmediate Wnt-3a activation of ATF2 signaling.
Romero D, Al-Shareef Z, Gorrono-Etxebarria I, et al., 2015, Dickkopf-3 regulates prostate epithelial cell acinar morphogenesis and prostate cancer cell invasion by limiting TGF-β-dependent activation of matrix metalloproteases., Carcinogenesis, Vol: 37, Pages: 18-29, ISSN: 1460-2180
Dickkopf-3 (Dkk-3) is a secreted protein whose expression is downregulated in many typesof cancer. Endogenous Dkk-3 is required for formation of acini in 3D cultures of prostateepithelial cells, where it inhibits transforming growth factor (TGF)-β/Smad signaling. Here,we examined the effects of Dkk-3 on the expression and activity of matrix metalloproteases(MMPs), which mediate the effects of TGF-β on extracellular matrix disassembly duringtissue morphogenesis and promote invasion of tumor cells. Silencing of Dkk-3 in prostateepithelial cells resulted in increased expression and enzyme activity of MMP-2 and MMP-9.Inhibition of MMP-9 partially restored normal acinar morphogenesis in Dkk-3-silencedRWPE-1 prostate epithelial cells. In prostate cancer, Dkk-3 inhibited TGF-β-dependentmigration and invasion. Inhibition was mediated by the Dkk-3 C-terminal cysteine-richdomain (Cys2), which also inhibited TGF-β-induced expression of MMP9 and MMP13. Incontrast, Dkk-3, but not Cys2, increased formation of normal acini in Dkk-3-silenced prostateepithelial cells. These observations highlight a role for Dkk-3 in modulating TGF-β/MMPsignals in the prostate, and suggest that the Dkk-3 Cys2 domain can be used as a basis fortherapies that target the tumor promoting effects of TGF-β signaling in advanced prostatecancer.
Bengoa-Vergniory N, Kypta RM, 2015, Canonical and noncanonical Wnt signaling in neural stem/progenitor cells, Cellular and Molecular Life Sciences, Vol: 72, Pages: 4157-4172, ISSN: 1420-682X
The first mammalian Wnt to be discovered,Wnt-1, was found to be essential for the development of alarge part of the mouse brain over 25 years ago. We havesince learned that Wnt family secreted glycolipoproteins,of which there are nineteen, which activate a diverse networkof signals that are particularly important duringembryonic development and tissue regeneration. Wnt signalsin the developing and adult brain can drive neural stemcell self-renewal, expansion, asymmetric cell division,maturation and differentiation. The molecular events takingplace after a Wnt binds to its cell-surface receptors arecomplex and, at times, controversial. A deeper understandingof these events is anticipated to lead to improvements inthe treatment of neurodegenerative diseases and stem cellbasedreplacement therapies. Here, we review the rolesplayed by Wnts in neural stem cells in the developingmouse brain, at neurogenic sites of the adult mouse and inneural stem cell culture models.
Bengoa-Vergniory N, Gorrono-Etxebarria I, Gonzalez-Salazar I, et al., 2014, A switch from canonical to noncanonical Wnt signaling mediates early differentiation of human neural stem cells, Stem Cells, Vol: 32, Pages: 3196-3208, ISSN: 1549-4918
Wnt/β-catenin signaling is essential for neurogenesis but less is known about β-catenin-independent Wnt signals. We show here that Wnt/activator protein-1 (AP-1) signaling drives differentiation of human embryonic stem cell and induced pluripotent stem cell-derived neural progenitor cells. Neuronal differentiation was accompanied by a reduction in β-catenin/Tcf-dependent transcription and target gene expression, increased levels and/or phosphorylation of activating transcription factor 2 (ATF2), cyclic AMP response element-binding protein, and c-Jun, and increased AP-1-dependent transcription. Inhibition of Wnt secretion using the porcupine inhibitors IWP-2 and Wnt-C59 blocked neuronal differentiation, while activation or inhibition of Wnt/β-catenin signaling had no effect. Neuronal differentiation increased expression of several Wnt genes, including WNT3A, silencing of which reduced differentiation. Addition of recombinant Wnt-3a to cells treated with IWP-2 or Wnt-C59 increased AP-1 levels and restored neuronal differentiation. The effects of Wnt-3a could not be blocked by addition of Dkk-1 or IWR-1, suggesting the involvement of noncanonical signaling. Consistent with this, restoration of neuronal differentiation by Wnt-3a was reduced by inhibition of Jun N-terminal kinase (JNK) and by gene silencing of ATF2. Together, these observations suggest that β-catenin-independent Wnt signals promote neural stem/progenitor cell differentiation in a signaling pathway involving Wnt-3a, JNK, and ATF2.
Jimenez Alfonso R, Gorrono-Etxebarria I, Rabano M, et al., 2014, Dickkopf-3 Alters the Morphological Response to Retinoic Acid During Neuronal Differentiation of Human Embryonal Carcinoma Cells, DEVELOPMENTAL NEUROBIOLOGY, Vol: 74, Pages: 1243-1254, ISSN: 1932-8451
Campa VM, Baltziskueta E, Bengoa-Vergniory N, et al., 2014, A screen for transcription factor targets of Glycogen Synthase Kinase-3 highlights an inverse correlation of NFκB and Androgen Receptor Signaling in Prostate Cancer, ONCOTARGET, Vol: 5, Pages: 8173-8187
Porlan E, Marti-Prado B, Manuel Morante-Redolat J, et al., 2014, MT5-MMP regulates adult neural stem cell functional quiescence through the cleavage of N-cadherin, NATURE CELL BIOLOGY, Vol: 16, Pages: 629-+, ISSN: 1465-7392
Kawano Y, Maeda Y, Motoshima T, et al., 2014, WNT/β-CATENIN SIGNALLING IS A POTENTIAL THERAPEUTIC TARGET FOR CASTRATE-RESISTANT PROSTATE CANCER., Annual Meeting of the American-Urological-Association (AUA), Publisher: ELSEVIER SCIENCE INC, Pages: E504-E505, ISSN: 0022-5347
Piva M, Domenici G, Iriondo O, et al., 2014, Sox2 promotes tamoxifen resistance in breast cancer cells, EMBO Molecular Medicine, Vol: 6, Pages: 66-79, ISSN: 1757-4676
Development of resistance to therapy continues to be a serious clinical problem in breast cancer management. Cancer stem/progenitor cells have been shown to play roles in resistance to chemo- and radiotherapy. Here, we examined their role in the development of resistance to the oestrogen receptor antagonist tamoxifen. Tamoxifen-resistant cells were enriched for stem/progenitors and expressed high levels of the stem cell marker Sox2. Silencing of the SOX2 gene reduced the size of the stem/progenitor cell population and restored sensitivity to tamoxifen. Conversely, ectopic expression of Sox2 reduced tamoxifen sensitivity in vitro and in vivo. Gene expression profiling revealed activation of the Wnt signalling pathway in Sox2-expressing cells, and inhibition of Wnt signalling sensitized resistant cells to tamoxifen. Examination of patient tumours indicated that Sox2 levels are higher in patients after endocrine therapy failure, and also in the primary tumours of these patients, compared to those of responders. Together, these results suggest that development of tamoxifen resistance is driven by Sox2-dependent activation of Wnt signalling in cancer stem/progenitor cells.
Bhandari S, Onganer PU, Romero D, et al., 2013, In vitro studies of the Wnt signalling pathways in FAP desmoid tumour, Joint Meeting of the Section-of-Surgery of the Royal-Society-of-Medicine / Annual Meeting of the Society-of-Academic-and-Research-Surgery, Publisher: WILEY-BLACKWELL, Pages: 38-38, ISSN: 0007-1323
Romero D, Kawano Y, Bengoa N, et al., 2013, Downregulation of Dickkopf-3 disrupts prostate acinar morphogenesis through TGF-β/Smad signalling, JOURNAL OF CELL SCIENCE, Vol: 126, Pages: 1858-1867, ISSN: 0021-9533
Kawano Y, Romero D, Bengora N, et al., 2013, LOSS OF DICKKOPF-3 EXPRESSION IMPAIRS PROSTATE ACINAR MORPHOGENESIS VIA ABERRANT TGF-β/SMAD SIGNALLING ACTIVATION, Annual Meeting of the American-Urological-Association (AUA), Publisher: ELSEVIER SCIENCE INC, Pages: E330-E330, ISSN: 0022-5347
Romero D, Kypta R, 2013, Dickkopf-3 function in the prostate: implications for epithelial homeostasis and tumor progression., Bioarchitecture, Vol: 3, Pages: 42-44
The tumor suppressor Dickkopf-3 (Dkk-3) is rather a unique molecule. Although it is related to the Dickkopf family of secreted Wnt antagonists, it does not directly inhibit Wnt signaling, and its function and mechanism of action are unknown. Endogenous Dkk-3 was recently found to be required to limit cell proliferation both in the developing mouse prostate and in 3D cultures of human prostate epithelial cells. Dkk-3 was further shown to modulate the response of normal prostate epithelial cells to transforming growth factor-β (TGF-β). These studies are consistent with a model in which Dkk-3 is required by normal cells to prevent the TGF-β switch from tumor suppressor to tumor promoter. Here, we discuss these findings and their potential impact on the development and progression of prostate cancer.
Darrington RS, Campa VM, Walker MM, et al., 2012, Distinct expression and activity of GSK-3α and GSK-3β in prostate cancer, INTERNATIONAL JOURNAL OF CANCER, Vol: 131, Pages: E872-E883, ISSN: 0020-7136
Kawano Y, Romera D, Bengoa N, et al., 2012, Crucial Role of Dickkopf-3 in Prostate Morphogenesis <i>in vitro</i> and <i>in vivo</i>, UROLOGY, Vol: 80, Pages: S81-S81, ISSN: 0090-4295
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