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wnt5a melanoma

Rochelle Shirin Sadeghi, Katarzyna Kulej, Rahul Singh Kathayat, Benjamin A Garcia, Bryan C Dickinson, Donita C Brady, Eric Witze
Wnt5a has been implicated in melanoma progression and metastasis, although the exact downstream signaling events that contribute to melanoma metastasis are poorly understood. Wnt5a signaling results in acyl protein thioesterase 1 (APT1) mediated depalmitoylation of pro-metastatic cell adhesion molecules CD44 and MCAM, resulting in increased melanoma invasion. The mechanistic details that underlie Wnt5a-mediated regulation of APT1 activity and cellular function remain unknown. Here, we show Wnt5a signaling regulates APT1 activity through induction of APT1 phosphorylation and we further investigate the functional role of APT1 phosphorylation on its depalmitoylating activity...
April 12, 2018: ELife
Anthony L Schwartz, Eric Dickerson, Nilesh Dagia, Ramiro Malgor, Kelly D McCall
Heightened co-expression and dysregulated signaling associated with Toll-like receptor 3 (TLR3) and Wnt5a is an integral component of solid tumors and hematological malignancies. Our previous findings in pancreatic cancer and melanoma suggest that inhibition of these pathways by a TLR3 signaling inhibitor, phenylmethimazole (C10), results in significantly decreased IL-6 levels, STAT3 phosphorylation, minimal cancer cell migration and reduced cancer cell growth in vitro and in vivo . In this study, we extended our earlier observations by performing studies in human breast cancer cells...
December 26, 2017: Oncotarget
Qi Liu, Hongda Zhu, Karthik Tiruthani, Limei Shen, Fengqian Chen, Keliang Gao, Xueqiong Zhang, Lin Hou, Degeng Wang, Rihe Liu, Leaf Huang
Development of an effective treatment against advanced tumors remains a major challenge for cancer immunotherapy. Approximately 50% of human melanoma is driven by B-Raf proto-oncogene mutation (BRAF mutant). Tumors with such mutation are desmoplastic, highly immunosuppressive, and often resistant to immune checkpoint therapies. We have shown that immunotherapy mediated by low-dose doxorubicin-induced immunogenic cell death was only partially effective for this type of tumor and not effective in long-term inhibition of tumor progression...
February 27, 2018: ACS Nano
Fei Zhao, Christine Xiao, Kathy S Evans, Tbalamayooran Theivanthiran, Nicholas DeVito, Alisha Holtzhausen, Juan Liu, Xiaojing Liu, David Boczkowski, Smita Nair, Jason W Locasale, Brent A Hanks
Despite recent advances, many cancers remain refractory to available immunotherapeutic strategies. Emerging evidence indicates that the tolerization of local dendritic cells (DCs) within the tumor microenvironment promotes immune evasion. Here, we have described a mechanism by which melanomas establish a site of immune privilege via a paracrine Wnt5a-β-catenin-peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling pathway that drives fatty acid oxidation (FAO) in DCs by upregulating the expression of the carnitine palmitoyltransferase-1A (CPT1A) fatty acid transporter...
January 16, 2018: Immunity
Abibatou Ndoye, Anna Budina-Kolomets, Curtis H Kugel, Marie R Webster, Amanpreet Kaur, Reeti Behera, Vito W Rebecca, Ling Li, Patricia A Brafford, Qin Liu, Y N Vashisht Gopal, Michael A Davies, Gordon B Mills, Xiaowei Xu, Hong Wu, Meenhard Herlyn, Michael C Nicastri, Jeffrey D Winkler, Maria S Soengas, Ravi K Amaravadi, Maureen E Murphy, Ashani T Weeraratna
Autophagy mediates resistance to various anticancer agents. In melanoma, resistance to targeted therapy has been linked to expression of Wnt5A, an intrinsic inhibitor of β-catenin, which also promotes invasion. In this study, we assessed the interplay between Wnt5A and autophagy by combining expression studies in human clinical biopsies with functional analyses in cell lines and mouse models. Melanoma cells with high Wnt5A and low β-catenin displayed increased basal autophagy. Genetic blockade of autophagy revealed an unexpected feedback loop whereby knocking down the autophagy factor ATG5 in Wnt5Ahigh cells decreased Wnt5A and increased β-catenin...
November 1, 2017: Cancer Research
Antonio Ahn, Aniruddha Chatterjee, Michael R Eccles
Treatment resistance in metastatic melanoma is a longstanding issue. Current targeted therapy regimes in melanoma largely target the proliferating cancer population, leaving slow-cycling cancer cells undamaged. Consequently, slow-cycling cells are enriched upon drug therapy and can remain in the body for years until acquiring proliferative potential that triggers cancer relapse. Here we overview the molecular mechanisms of slow-cycling cells that underlie treatment resistance in melanoma. Three main areas of molecular reprogramming are discussed that mediate slow cycling and treatment resistance...
June 2017: Molecular Cancer Therapeutics
Anthony L Schwartz, Eric Dickerson, Nilesh Dagia, Ramiro Malgor, Kelly D McCall
Heightened co-expression and dysregulated signaling associated with Toll-like receptor 3 (TLR3) and Wnt5a is an integral component of solid tumors and hematological malignancies. Our previous findings in pancreatic cancer and melanoma suggest that inhibition of these pathways by a TLR3 signaling inhibitor, phenylmethimazole (C10), results in significantly decreased IL-6 levels, STAT3 phosphorylation, minimal cancer cell migration and reduced cancer cell growth in vitro and in vivo. In this study, we extended our earlier observations by performing studies in human breast cancer cells...
July 1, 2016: Oncotarget
Stefanie Thiele, Tilman D Rachner, Martina Rauner, Lorenz C Hofbauer
Wnt signaling is critical for tumorigenesis and skeletal remodeling. However, its contribution to the formation of metastatic bone lesions remains poorly defined. One major challenge of unraveling its role in cancer progression is the high complexity of Wnt signaling, which includes numerous ligands, receptors, and inhibitors, with intricate biological effects and specific signaling pathways depending on the cellular context. In this perspective, we summarize the role of the noncanonical Wnt ligand WNT5A in the development and metastatic process of osteotropic cancer entities...
August 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Rickard Linnskog, Purusottam Mohapatra, Farnaz Moradi, Chandra Prakash Prasad, Tommy Andersson
Increased expression and signalling of WNT5A and interleukin-6 (IL-6) have both been shown to promote melanoma progression. Here, we investigated the proposed existence of a WNT5A-IL-6 positive feedback loop that drives melanoma migration and invasion. First, the HOPP algorithm revealed that the invasive phenotype of cultured melanoma cells was significantly correlated with increased expression of WNT5A or IL-6. In three invasive melanoma cell lines, endogenous WNT5A protein expression was related to IL-6 protein secretion...
June 21, 2016: Oncotarget
Farnaz Moradi, Pontus Berglund, Rickard Linnskog, Karin Leandersson, Tommy Andersson, Chandra Prakash Prasad
Overexpression of wingless-type MMTV integration site family 5A (WNT5A) plays a significant role in melanoma cancer progression; however, the mechanism(s) involved remains unknown. In breast cancer, the human antigen R (HuR) has been implicated in the regulation of WNT5A expression. Here, we demonstrate that endogenous expression of WNT5A correlates with levels of active HuR in HTB63 and WM852 melanoma cells and that HuR binds to WNT5A messenger RNA in both cell lines. Although the HuR inhibitor MS-444 significantly impaired migration in both melanoma cell lines, it reduced WNT5A expression only in HTB63 cells, as did small interfering RNA knockdown of HuR...
June 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
Yuanyuan Tang, Ke Cao, Qi Wang, Jia Chen, Rui Liu, Shaohua Wang, Jianda Zhou, Huiqing Xie
Ceramide synthases (CerSs) have been shown to regulate numerous aspects of cancer development. CerS6 has been suggested to be involved in cancer etiology. However, little is known concerning the exact effect of CerS6 on the malignant behavior of melanoma, including glycolysis, proliferation and invasion. In the present study, we found that the expression of CerS6 was low in the melanoma cell lines, including WM35, WM451 and SK-28, and the expression level was related to the malignanct behavior of the melanoma cell lines...
May 2016: Oncology Reports
Natalia Brenda Fernández, Daniela Lorenzo, María Elisa Picco, Gastón Barbero, Leonardo Sebastián Dergan-Dylon, María Paula Marks, Hernán García-Rivello, Liliana Gimenez, Vivian Labovsky, Luca Grumolato, Pablo Lopez-Bergami
The Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is primarily expressed by neural crest cells during embryogenesis. Following a complete downregulation after birth, ROR1 was shown to re-express in various types of cancers. Little is known about ROR1 expression and function in melanoma. Here we show that ROR1 is aberrantly expressed in both melanoma cell lines and tumors and that its expression associates with poor Post-Recurrence Survival of melanoma. Using gain- and loss-of-function approaches we found that ROR1 enhances both anchorage-dependent and -independent growth of melanoma cells...
November 2016: Molecular Carcinogenesis
Chandra Prakash Prasad, Purusottam Mohapatra, Tommy Andersson
In recent years, scientists have advocated the use of targeted therapies in the form of drugs that modulate genes and proteins that are directly associated with cancer progression and metastasis. Malignant melanoma is a dreadful cancer type that has been associated with the rapid dissemination of primary tumors to multiple sites, including bone, brain, liver and lungs. The discovery that approximately 40%-50% of malignant melanomas contain a mutation in BRAF at codon 600 gave scientists a new approach to tackle this disease...
2015: Cancers
Koichi Kobayashi, Kunihiko Hiraishi
Attractors in gene regulatory networks represent cell types or states of cells. In system biology and synthetic biology, it is important to generate gene regulatory networks with desired attractors. In this paper, we focus on a singleton attractor, which is also called a fixed point. Using a Boolean network (BN) model, we consider the problem of finding Boolean functions such that the system has desired singleton attractors and has no undesired singleton attractors. To solve this problem, we propose a matrix-based representation of BNs...
November 2014: IEEE/ACM Transactions on Computational Biology and Bioinformatics
Robert Hooper, Xuexin Zhang, Marie Webster, Christina Go, Joseph Kedra, Katie Marchbank, Donald L Gill, Ashani T Weeraratna, Mohamed Trebak, Jonathan Soboloff
The incidence of malignant melanoma, a cancer of the melanocyte cell lineage, has nearly doubled in the past 20 years. Wnt5A, akey driver of melanoma invasiveness, induces Ca2 signals. To understand how store-operated calcium entry (SOCE) contributes to Wnt5A-induced malignancy in melanoma models, we examined the expression and function of STIM1 and Orai1 in patient-derived malignant melanoma cells, previously characterized as either highly invasive (metastatic) or noninvasive. Using both fluorescence microscopy and electrophysiological approaches, we show that SOCE is greatly diminished in invasive melanoma compared to its level in noninvasive cell types...
August 2015: Molecular and Cellular Biology
Alisha Holtzhausen, Fei Zhao, Kathy S Evans, Masahito Tsutsui, Ciriana Orabona, Douglas S Tyler, Brent A Hanks
The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown...
September 2015: Cancer Immunology Research
W Wang, N Snyder, A J Worth, I A Blair, E S Witze
Expression of the Wnt ligand Wnt5a is frequently elevated in melanoma and is thought to be a critical regulator of cell movement during metastasis. However, the mechanisms regulating its expression are unknown. We find that the level of secreted Wnt5a varies by as much as 10-fold between cell lines and correlates more strongly with invasion than total cellular levels. Our results indicate that the RNA helicase Mov10 plays a role in Wnt5a synthesis and secretion. Inhibition of Mov10 increases secreted Wnt5a levels in melanoma cells by increasing Wnt5a synthesis and acylation...
2015: Oncogenesis
Wei Wang, Kristin B Runkle, Samantha M Terkowski, Rachel I Ekaireb, Eric S Witze
Wnt5a signaling regulates polarized cell behavior, but the downstream signaling events that promote cell polarity are not well understood. Our results show that Wnt5a promotes depalmitoylation of the melanoma cell adhesion molecule (MCAM) at cysteine 590. Mutation of Cys-590 to glycine is sufficient to polarize MCAM localization, similar to what is observed with Wnt5a stimulation. Inhibition of the depalmitoylating enzyme APT1 blocks Wnt5a-induced depalmitoylation, asymmetric MCAM localization, and cell invasion...
June 19, 2015: Journal of Biological Chemistry
Mizuho Fukunaga-Kalabis, Denitsa M Hristova, Joshua X Wang, Ling Li, Markus V Heppt, Zhi Wei, Alexandra Gyurdieva, Marie R Webster, Masahiro Oka, Ashani T Weeraratna, Meenhard Herlyn
Multipotent stem cells with neural crest-like properties have been identified in the dermis of human skin. These neural crest stem cell (NCSC)-like cells display self-renewal capacity and differentiate into neural crest derivatives, including epidermal pigment-producing melanocytes. NCSC-like cells share many properties with aggressive melanoma cells, such as high migratory capabilities and expression of the neural crest markers. However, little is known about which intrinsic or extrinsic signals determine the proliferation or differentiation of these neural crest-like stem cells...
June 2015: Journal of Investigative Dermatology
Yun Yang, Qiufang Qian
Melanoma is rare in children, but its incidence appears to be increasing. Melanoma accounts for the highest mortality among all skin cancer types. This disease is characterized by high-grade malignancy, easy metastasis, poor prognosis, and high death rate. Melanoma in children may be biologically different from that in adults. Therefore, novel biomarkers need to be developed to understand the mechanism by which melanoma cells migrate and infiltrate. Such biomarkers will also be useful for the molecular recognition and targeted therapy of melanoma...
November 2014: Journal of Cancer Research and Therapeutics
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