Differentiation generates paracrine cell pairs that maintain basaloid mouse mammary tumors: proof of concept. Canonical Wnt signaling is required for pancreatic carcinogenesis. Cancer Cell 2010; 18: 606–618. The ER resident acyl-transferase Porcupine is required for the attachment of palmitoleic acid to Wnt ligands.19 Thereafter, lipid-modified Wnt ligands bind to the transmembrane protein Evi/Wls and are shuttled to the plasma membrane via the Golgi apparatus.20, 21, 22 The transport of Wnts from the ER to the Golgi is assisted by p24 proteins.23, 24 After secretion of Wnt ligands, Evi/Wls is undergoing clathrin based endocytosis and is recycled to the Golgi apparatus by the retromer complex.25, 26 Finally, Evi/Wls is transported back to the ER to re-engage in Wnt secretion.22. Rusan NM, Peifer M . Webster MR, Xu M, Kinzler KA, Kaur A, Appleton J, Connell MPO et al. Latres E, Chiaur DS, Pagano M . Park J-I, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M et al. 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Figure 1: The tumor microenvironment consists of cancer cells as well as many different types of stromal cells, including fibroblasts, T cells, neutrophils, macrophages, and endothelial cells. Nusse R, Varmus HE . Luga V, Zhang L, Viloria-Petit AM, Ogunjimi A a, Inanlou MR, Chiu E et al. Cell 1982; 31: 99–109. Yu J, Chia J, Canning CA, Jones CM, Bard FA, Virshup DM . Genes Dev 2014; 28: 305–316. Geyer FC, Lacroix-Triki M, Savage K, Arnedos M, Lambros MB, MacKay A et al. Chien AJ, Moore EC, Lonsdorf AS, Kulikauskas RM, Rothberg BG, Berger AJ et al. Google Scholar. It was shown to inhibit the growth of human tumor xenografts and to synergize with standard-of-care therapeutic agents,187 but first data from clinical studies suggested adverse effects on skeletal constitution.188 This finding was considered as an on-target effect of Wnt inhibition since Wnt signaling has a key role in bone development and disease.189 Currently, OMP18R5 is studied in phase I clinical trials alone or in combination with taxanes in breast and pancreatic cancer, as well as non-small cell lung cancer. Loilome W, Bungkanjana P, Techasen A, Namwat N, Yongvanit P, Puapairoj A et al. 1, 2017, Reactive oxygen species (ROS), now appreciated for their cellular signaling capabilities, have a dual role in cancer. Wnt gradient formation requires retromer function in Wnt-producing cells. 2015, p NCT02413853. Wnt/STOP has also been proposed to affect chromosomal stability, cell division and endolysosomal biogenesis.57, 58, 59 It remains to be further elucidated whether tissue- and time-dependent preferences for Wnt/STOP or transcriptional Wnt responses exist and can be exploited for cancer therapy. (a) In canonical Wnt signaling, absence of Wnt ligands (Wnt signaling inactive state, left) leads to phosphorylation of β-catenin by the destruction complex, which contains the scaffold protein Axin, APC and the kinases GSK3β and casein kinase (CK1α). Google Scholar. Furthermore, we review the current progress on targeting the Wnt pathway. Key protein regulators of ferroptosis are shown in blue, while se... Colleen R. Reczek and Navdeep S. ChandelVol. EMBO Rep 2011; 12: 1265–1272. While many human genes are dependent on introns and splicing for normal levels of gene expression, naturally intronless genes exist with a unique metabolism that allows for intron -independent gene expression. Sci Signal 2012; 5: ra3. Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis. Christie M, Jorissen RN, Mouradov D, Sakthianandeswaren A, Li S, Day F et al. Huang Y-L, Anvarian Z, Döderlein G, Acebron SP, Niehrs C . Nat Med 2013; 19: 179–192. Gene view. Novel compounds aimed at modulating the WNT signaling pathway using diverse mechanisms are currently under investigation in preclinical/early clinical studies. Nat Rev Drug Discov 2014; 13: 513–532. J Cell Physiol 2012; 227: 1960–1971. It also uses cookies for the purposes of performance measurement. An overview of small molecular inhibitors and antibodies that are currently in clinical testing is presented in Figure 3 and Table 1. Wnt/Planar cell polarity signaling: a new paradigm for cancer therapy. Two Wnt5a analog small peptides, Foxy-5 and Box-5 have been developed to either activate or inhibit Wnt5a-dependent signaling, thereby reducing metastasis in selected tumors. Dishevelled: the hub of Wnt signaling. About 25% of melanomas arise from benign nevi (commonly known as moles) which typically consist of quiescent BRAFV600E or NRASQ61K mutant melanocytes that have undergone a process of oncogene induced senescence105, 106 (reviewed in Jones and Cichowski107). Canonical Wnt signaling is active in CLL cells and its inhibition increases apoptosis in vitro.102 Next to frequent silencing of Wnt inhibiting factors such as DKK1/2,103 somatic mutations in Wnt pathway related genes (for example, FZD5, BCL9) were found in 14% of studied cases.104 Knockdown of mutated Wnt pathway members reduced cell viability in CLL cells carrying the targeted Wnt pathway alteration, while those without Wnt pathway mutations remained unaffected.104 These findings demonstrate that a subset of CLL is dependent on active Wnt signaling for survival. 3.2. Wnt-mediated protein stabilization ensures proper mitotic microtubule assembly and chromosome segregation. Binding of Wnt5a leads to the formation of the ROR2 receptor complex (Figure 1b). Cell 2010; 143: 1136–1148. TERT expression was found to be directly enhanced by binding of β-catenin to its promoter region and thereby links telomerase activity to Wnt signaling.145 The R-spondin receptor Lgr5 is a marker of intestinal stem cells and can fuel tumor growth when APC is deleted in these cells.146 Lineage tracing experiments demonstrate that single Lgr5-positive cells can give rise to additional Lgr5-positive cells and other cell types in colon adenoma, indicating that Lgr5 is a potential cancer stem cell marker.147 Myant et al.148 show that RAC1 is required for expansion of the Lgr5 population after APC loss. Vol. 2015;65:87-108 18. Nature 2015; 523: 231–235. Giambra V, Jenkins CE, Lam SH, Hoofd C, Belmonte M, Wang X et al. Association of the APC tumor suppressor protein with catenins. Katoh M . AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Targeting of Fzd2 by a specific antibody reduces tumor growth and metastasis in a xenograft mouse model of colon cancer.166. Can we safely target the WNT pathway? Nature 2012; 493: 106–110. Differential niche and Wnt requirements during acute myeloid leukemia progression. Figure 4: Antioxidant therapy and localization of reactive oxygen species (ROS). Dev Cell 2004; 7: 525–534. Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma. Cancer 1989; 63: 550–555. However, substantial phenotypic differences between cancers originating … Oncogene Figure 3. Oncogene 2006; 25: 7531–7537. Kikuchi A, Yamamoto H, Sato A, Matsumoto S . Periostin interacts with Wnt1 and Wnt3a, thereby inducing Wnt signaling and sustaining a CSC phenotype.151 In another study, MMP3 secreted by mammary epithelial cells was found to stimulate canonical Wnt signaling in mammary stem cells by sequestration of Wnt5b, thereby counteracting the inhibitory effect of the non-canonical Wnt pathway.152 CD44v6 was described as another CSC marker in colorectal cancer and its expression is promoted by canonical Wnt signaling and cytokines secreted from tumor-associated cells, resulting in increased metastatic capacity.153, Recently, several studies uncovered potential links between non-coding RNAs and Wnt signaling in cancer stem cells. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Google Scholar. Nat Cell Biol 2010; 12: 468–476. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. Sci Transl Med 2012; 4: 148ra117. Metcalfe C, Mendoza-Topaz C, Mieszczanek J, Bienz M . Sharma R . Rspo2/Int7 regulates invasiveness and tumorigenic properties of mammary epithelial cells. Overcoming immune evasion by cancer cells is a promising therapeutic approach and immune checkpoint blockade was shown to be highly effective in the treatment of melanoma173 and other tumor types.174, 175 Wnt signaling controls proliferation, maturation and differentiation of T-cells and dendritic cells,176 but a role of tumor intrinsic Wnt signaling in immune evasion has only recently emerged. Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. EMT: when epithelial cells decide to become mesenchymal-like cells. First results from a phase I clinical trial of Foxy-5 suggest a good tolerability.199. Merlos-Suárez A, Barriga FM, Jung P, Iglesias M, Céspedes MV, Rossell D et al. EMT describes the process by which polarized epithelial cells transform into migratory mesenchymal cells with invasive properties.161, 162 Transcriptional factors that are responsible for EMT include, among others, SNAI2. Guo W, Lasky JL, Chang C-J, Mosessian S, Lewis X, Xiao Y et al. LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy. DNA is the genetic “blueprint” in each cell. Three essential hallmarks define ferroptosis, namely: the loss of lipid peroxide repair capacity by the ...Read More. Proc Natl Acad Sci USA 2003; 100: 15853–15858. Active Wnt proteins are secreted on exosomes. Zhang Y, Morris JP, Yan W, Schofield HK, Gurney A, Simeone DM et al. Mitotic Wnt signaling promotes protein stabilization and regulates cell size. Cell 2014; 158: 157–170. Sci Signal 2013; 6: pe11. Genetic alterations of WNT signaling occur relatively rarely in PDAC (Cancer Genome Atlas Res. We describe recently discovered Wnt pathway components and novel functions of the Wnt pathway for cancer stemness, metastasis and immune surveillance. Another example is Robinow syndrome, associated with mutations in three different Wnt signaling components: ROR2 … (2021), Oncogene Boulter L, Guest R V, Kendall TJ, Wilson DH, Wojtacha D, Robson AJ et al. Klauzinska M, Baljinnyam B, Raafat A, Rodriguez-Canales J, Strizzi L, Endo Greer Y et al. Giannakis M, Hodis E, Jasmine Mu X, Yamauchi M, Rosenbluh J, Cibulskis K et al. Loss of function of Wnt pathway components, particularly APC, have been linked to CIN by multiple mechanisms.77, 78, 79 Although direct interactions of APC with the cytoskeleton and the transcriptional Wnt response via β-catenin are known routes to CIN, Wnt/STOP was introduced as new mechanism: Ertych et al. Wu Z-Q, Li X-Y, Hu CY, Ford M, Kleer CG, Weiss SJ . The self-renewal potential of cancer cells is described by the cancer stemness model and has been used to explain many malignant phenotypes.143 Although the concept of cancer stemness is still controversially discussed, the vital role of the Wnt pathway for the function of normal and cancer stem cells is commonly accepted (reviewed in Reya and Clevers144).