Cancer ScienceVolume 111, Issue 3 p. 764-765 IN THIS ISSUEOpen Access In this Issue Volume 111, Issue 3, March 2020 First published: 07 March 2020 https://doi.org/10.1111/cas.14047AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Discovery of chemical probes that suppress Wnt/β-catenin signaling through high-throughput screening Abnormalities in the Wnt/β-catenin signaling pathway have been noted in a variety of cancers, including colorectal carcinoma (CRC), endometrial carcinoma, esophageal carcinoma, and diffuse large B-cell lymphoma. The frequency of these abnormalities varies, but in cancers like CRC it has been reported as high as 90%. The Wnt/β-catenin signaling pathway and Wnt target genes are known to be proto-oncogenes, cell cycle regulators, and stem cell markers, but there is growing evidence that the pathway also plays a significant role in the immune system. Further improvements in cancer immunotherapy may depend on increased targeting of the Wnt/β-catenin signaling pathway. In this study, Yamaguchi et al comprehensively review the current state of Wnt inhibitors. They cover the six classes, including tankyrase inhibitors, porcupine inhibitors, CK1α activators, inhibitors of β-catenin-TCF interaction, inhibitors of transcriptional coactivators of β-catenin, and inducers of β-catenin degradation. They also discuss the different models of reporter assays that can be used in high-throughput screening (HTS). https://onlinelibrary.wiley.com/doi/10.1111/cas.14297 YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that acts with other members of the ErbB family of proteins to induce signaling pathways like PI3K-AKT and MAPK to promote cell proliferation and survival. Several cancers, breast cancer in particular, can be driven by the overexpression of HER2. HER2-targeted drugs, like trastuzumab, have improved outcomes in breast cancer patients, but many of these patients recur because resistance develops. There are already new drugs like neratinib, an irreversible tyrosine kinase inhibitor, that can treat these resistant tumors, but eventually resistance will also develop to neratinib. In this study, Takeda et al have developed neratinib-resistant cells in order to study how this resistance develops. They found that YES1 was upregulated in the neratinib-resistant cell lines and appeared to be responsible for the resistance. Further, they showed that dasatinib, a SRC inhibitor that targets YES1, overcame the resistance. This provides valuable insight into the development of resistance and provides a solution when the resistance develops. https://onlinelibrary.wiley.com/doi/10.1111/cas.14289 Epstein-Barr virus-encoded latent membrane protein 1 promotes extracellular vesicle secretion through syndecan-2 and synaptotagmin-like-4 in nasopharyngeal carcinoma cells Nasopharyngeal carcinoma (NPC) is particularly prevalent in Southeast Asia and in southern China. Progression of NPC is strongly correlated with the presence of Epstein-Barr virus (EBV). EBV’s oncogenic properties have been attributed to the protein, EBV-encoded latent membrane protein 1 (LMP1). Transmission of extracellular vesicles laden with EBV-encoded LMP1 activates many signaling pathways that promote tumor invasion and progression in the tumor microenvironment (TME). In this study, Liao et al examined the molecular mechanism by with LMP1 promotes EV secretion. They confirmed that LMP1 does in fact promote EV secretion and determined that this was due to the upregulation of syndecan-2 (SDC2) and synaptotagmin-like-4 (SYTL4). SDC2 promoted formation of EVs, while SYTL4 promoted secretion of EVs. Furthermore, EVs induced by LMP1 led to tumor growth in vivo. This study provides valuable mechanistic information into the progression and metastasis of NPC. https://onlinelibrary.wiley.com/doi/10.1111/cas.14305 From our sister journal—A Foxp3 variant, neutral at steady state, enhances antitumor immunity Immune surveillance of tumors and efficacy of tumor immunotherapies are restricted by natural mechanisms of immune tolerance, and highly variable between individuals. The role of host-, rather than tumor-genetics underlying this variance has been overlooked. In this issue, Almeida-Santos et al. tested three tumor models with different immunogenicity and invasiveness in mice carrying the commonly used Foxp3fGFP allele, which is neutral at steady state in reference strains. The inspection of Foxp3fGFP allele revealed the cryptic immunogenicity of a primary tumor otherwise fully tolerated, delayed metastasis dissemination of an invasive tumor, and transformed anti-CTLA4 therapy of a resistant melanoma from inefficient to efficacious. These findings reinforce the notion that experimental variations can be related to reporter alleles, and highlight that identification of weak hypomorphs in genes related to immune regulation may guide cancer prognostics and therapeutic strategies. Reprinted with Permission: Eur J Immunol 2020, https://doi.org/10.1002/eji.201948251 References Almeida-Santos J, Bergman ML, Amendoeira Cabral I, Correia V, Caramalho Í, Demengeot J. Eur. J. Immunol. 2020. https://doi.org/10.1002/eji.201948251 Volume111, Issue3March 2020Pages 764-765 ReferencesRelatedInformation
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