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Leonie S. Young – One of the best experts on this subject based on the ideXlab platform.

  • po 507 adam22 as a therapeutic target for endocrine resistant metastatic breast cancer
    Poster Presentation, 2018
    Co-Authors: B. O'doherty, Sinead Cocchiglia, Damir Vareslija, Sara Charmsaz, Jarlath C. Bolger, Arnold D K Hill, Leonie S. Young

    Abstract:

    Introduction The development of endocrine resistance is a major hurdle for the treatment of oestrogen receptor positive (ER+) breast cancer. One of the key contributors to this resistant phenotype is overexpression of the nuclear receptor coactivator SRC-1, which in turn has been shown to promote metastatic disease. Using CHIP-seq and microarray studies, the neuronal protein ADAM22 (A Disintegrin And Metalloproteinase) was identified as a potential pro-metastatic SRC-1 regulated gene in endocrine resistant cell lines. ADAM22 expression promotes both migration and de-differentiation, key hallmarks of metastasis. While clinically, elevated ADAM22 expression predicts poor disease free survival. Here, both the role of ADAM22 in metastatic development and the clinical potential of ADAM22 as a biomarker and therapeutic target were explored. Material and methods The functional effect of ADAM22 modulation on anchorage independent growth and mammosphere formation was investigated using CRISPR/Cas9 knockout and lentiviral overexpression in the endocrine resistant LY2 cell line. To examine the clinical relevance of ADAM22 as a biomarker, ADAM22 expression was examined in matched primary breast and metastatic cancer tissues. A small peptide mimetic of the ADAM22 endogenous ligand LGI1 (LGIMIM) was designed and explored as a potential anti-ADAM22 therapeutic both in vitro and in vivo . Results and discussions ADAM22 expression promotes anchorage independent growth and mammosphere formation, suggesting ADAM22 contributes to both the survival of metastatic cells and their ability to colonise distant sites. ADAM22 expression was significantly higher in primary breast tumours which went on to metastasise versus primaries which did not. A significant increase in ADAM22 expression was found in brain metastatic tissue compared to matched primary tissue, suggesting ADAM22 may prime endocrine resistant cancer cells to colonise the brain. LGIMIM treatment was sufficient to inhibit ADAM22 mediated phenotypes in vitro and to reduce metastatic burden in a xenograft model of endocrine resistance in vivo . Conclusion ADAM22 is a promising biomarker and therapeutic target for endocrine resistant breast cancer.

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  • abstract p3 05 02 global characterisation of the src 1 transcriptome and rational drug design results in the identification of a novel peptide targeting adam22 in endocrine resistance
    Cancer Research, 2015
    Co-Authors: Jarlath C. Bolger, Damir Vareslija, Arnold D K Hill, Damian Mccartan, Ailis Fagan, Christopher Byrne, Marie Mcilroy, Peadar Ogaora, Leonie S. Young

    Abstract:

    In spite of therapeutic advances, up to 25% of luminal breast cancers will eventually develop resistance to endocrine therapy and develop metastatic disease. The underlying mechanism causing ER-positive, steroid responsive tumours to develop a resistant, metastatic phenotype remains unresolved. Previous work from our group and others has identified the P160 protein SRC-1 as a significant predictor of recurrence on endocrine therapy. The purpose of this study is to further examine downstream SRC-1 targets in the context of endocrine resistant breast cancer. We adopted a global approach to define the transcriptional targets of SRC-1. SRC-1 ChIP sequencing in endocrine resistant luminal B breast cancer cells was combined with SRC-1 gene expression array analysis. This identified a number of pathways significantly elevated following tamoxifen treatment, including a number involved in cellular adhesion. From these pathways, A Disintegrin And Metalloproteinase-22 (ADAM22) was selected for further study. Knockout studies confirmed ADAM22 as a tamoxifen dependent SRC-1 target gene. Functional assays including migration, three dimensional cell culture and adhesion independence growth assays confirmed a role for ADAM22 in promoting a migratory, aggressive phenotype. Samples from two separate TMAs comprising over 1,000 patients confirmed that ADAM22 is associated with poor disease free survival in breast cancer patients. LGI1 is a naturally occurring neuropeptide which acts on an inhibitory manner on ADAM22 in the central nervous system. Using molecular modelling, a novel peptide mimetic targeting the disintegrin binding domain of ADAM22 was designed. Treatment with this peptide mimetic restored endocrine resistant cells to a less aggressive, sensitive phenotype, similar to the effect seen with knockdown of ADAM22. Moreover in an endocrine resistant xenograft model, treatment with the LGI1 mimetic significantly reduced primary and metastatic tumour burden in tamoxifen treated animals. We have used next-generation sequencing techniques to identify a novel therapeutic target in endocrine resistant, metastatic breast cancer. Rational drug design has been used to manufacture a therapeutic peptide against ADAM22. A combination of in vitro, in vivo and patient studies has confirmed a role for ADAM22 in metastatic breast cancer. Our novel peptide mimetic may form a future basis for targeting ADAM22 in endocrine resistant disease. Citation Format: Jarlath C Bolger, Damian McCartan, Damir Vareslija, Ailis Fagan, Christopher Byrne, Marie McIlroy, Peadar O9Gaora, Arnold D Hill, Leonie S Young. Global characterisation of the SRC-1 transcriptome and rational drug design results in the identification of a novel peptide targeting ADAM22 in endocrine resistance [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-02.

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  • ADAM22 as a prognostic and therapeutic drug target in the treatment of endocrine-resistant breast cancer.
    Vitamins & Hormones, 2013
    Co-Authors: Jarlath C. Bolger, Leonie S. Young

    Abstract:

    The development of breast cancer resistance to endocrine therapies may result from an increase in cellular plasticity, permitting the emergence of a hormone-independent tumor. ADAM proteins are multidomain transmembrane proteins that have a diverse array of functions in both natural physiology and disease. A number of ADAM proteins have been implicated in the occurrence of breast cancer, including ADAM 9, ADAM12, ADAM15, ADAM17, ADAM22, and ADAM28. ADAM22 expression is driven by the coactivator protein SRC-1 in response to tamoxifen treatment in the resistant setting. ADAM22 is an ER-independent predictor of disease-free survival. LGI1 is a neuropeptide that binds ADAM22 in the nervous system. In addition to being a ligand for ADAM11, ADAM22, and ADAM23, LGI1 may play a role as a tumor suppressor. Furthermore, LGI1 may act to reduce cell migration and may impair proliferation. Therapies based on LGI1 may provide a building block for future therapies in ADAM22-positive breast cancer.

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Masaki Fukata – One of the best experts on this subject based on the ideXlab platform.

  • Functional phylogenetic analysis of LGI proteins identifies an interaction motif crucial for myelination
    Development, 2014
    Co-Authors: Linde Kegel, Martine Jaegle, Siska Driegen, Eerik Aunin, Kris Leslie, Yuko Fukata, Masahiko Watanabe, Masaki Fukata, Dies Meijer

    Abstract:

    The cellular interactions that drive the formation and maintenance of the insulating myelin sheath around axons are only partially understood. Leucine-rich glioma-inactivated (LGI) proteins play important roles in nervous system development and mutations in their genes have been associated with epilepsy and amyelination. Their function involves interactions with ADAM22 and ADAM23 cell surface receptors, possibly in apposing membranes, thus attenuating cellular interactions. LGI4-ADAM22 interactions are required for axonal sorting and myelination in the developing peripheral nervous system (PNS). Functional analysis revealed that, despite their high homology and affinity for ADAM22, LGI proteins are functionally distinct. To dissect the key residues in LGI proteins required for coordinating axonal sorting and myelination in the developing PNS, we adopted a phylogenetic and computational approach and demonstrate that the mechanism of action of LGI4 depends on a cluster of three amino acids on the outer surface of the LGI4 protein, thus providing a structural basis for the mechanistic differences in LGI protein function in nervous system development and evolution.

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  • autoantibodies to epilepsy related lgi1 in limbic encephalitis neutralize lgi1 adam22 interaction and reduce synaptic ampa receptors
    The Journal of Neuroscience, 2013
    Co-Authors: Toshika Ohkawa, Yuko Fukata, Masahiko Watanabe, Miwako Yamasaki, Taisuke Miyazaki, Norihiko Yokoi, Hiroshi Takashima, Osamu Watanabe, Masaki Fukata

    Abstract:

    More than 30 mutations in LGI1, a secreted neuronal protein, have been reported with autosomal dominant lateral temporal lobe epilepsy (ADLTE). Although LGI1 haploinsufficiency is thought to cause ADLTE, the underlying molecular mechanism that results in abnormal brain excitability remains mysterious. Here, we focused on a mode of action of LGI1 autoantibodies associated with limbic encephalitis (LE), which is one of acquired epileptic disorders characterized by subacute onset of amnesia and seizures. We comprehensively screened human sera from patients with immune-mediated neurological disorders for LGI1 autoantibodies, which also uncovered novel autoantibodies against six cell surface antigens including DCC, DPP10, and ADAM23. Our developed ELISA arrays revealed a specific role for LGI1 antibodies in LE and concomitant involvement of multiple antibodies, including LGI1 antibodies in neuromyotonia, a peripheral nerve disorder. LGI1 antibodies associated with LE specifically inhibited the ligand-receptor interaction between LGI1 and ADAM22/23 by targeting the EPTP repeat domain of LGI1 and reversibly reduced synaptic AMPA receptor clusters in rat hippocampal neurons. Furthermore, we found that disruption of LGI1-ADAM22 interaction by soluble extracellular domain of ADAM22 was sufficient to reduce synaptic AMPA receptors in rat hippocampal neurons and that levels of AMPA receptor were greatly reduced in the hippocampal dentate gyrus in the epileptic LGI1 knock-out mouse. Therefore, either genetic or acquired loss of the LGI1-ADAM22 interaction reduces the AMPA receptor function, causing epileptic disorders. These results suggest that by finely regulating the synaptic AMPA receptors, the LGI1-ADAM22 interaction maintains physiological brain excitability throughout life.

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  • Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy
    Proceedings of the National Academy of Sciences of the United States of America, 2010
    Co-Authors: Yuko Fukata, Norihiko Yokoi, Kathryn Lynn Lovero, Tsuyoshi Iwanaga, Atsushi Watanabe, Katsuhiko Tabuchi, Ryuichi Shigemoto, Roger A. Nicoll, Masaki Fukata

    Abstract:

    Epilepsy is a devastating and poorly understood disease. Mutations in a secreted neuronal protein, leucine-rich glioma inactivated 1 (LGI1), were reported in patients with an inherited form of human epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF). Here, we report an essential role of LGI1 as an antiepileptogenic ligand. We find that loss of LGI1 in mice (LGI1−/−) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3. Moreover, heterozygous mice for the LGI1 mutation (LGI1+/−) show lowered seizure thresholds. Extracellularly secreted LGI1 links two epilepsy-related receptors, ADAM22 and ADAM23, in the brain and organizes a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor–mediated synaptic transmission in the hippocampus. Thus, LGI1 may serve as a major determinant of brain excitation, and the LGI1 gene-targeted mouse provides a good model for human epilepsy.

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Ulrike Novak – One of the best experts on this subject based on the ideXlab platform.

  • differential coding potential of adam22 mrnas
    Gene, 2007
    Co-Authors: Nathan Godde, Giovanna M Dabaco, Lucy Paradiso, Ulrike Novak

    Abstract:

    Abstract ADAM22 is one of three catalytically inactive ADAM family members highly expressed in the brain. Preliminary functional studies suggest possible roles in epilepsy and myelination. We report an additional eight new splice variants of human ADAM22. Analysis of the altered splicing patterns of ADAM22 mRNAs in glioma allows us to suggest alternate splicing patterns in normal brain compared to glioma may represent differential use of exon 32. We also report diversity in the 5′ leader sequences of ADAM22 mRNAs as a consequence of alternate transcriptional initiation sites. ADAM22 has an additional transcriptional initiation element producing transcripts lacking the exon 1 sequence including the signal peptide. Variable transcriptional initiation in exon 1 produces a range of ADAM22 5′ leader sequence lengths, all of which are significantly longer than those described in NCBI reference sequences. Longer 5′ leader sequences contain a second upstream AUG codon which acts to inhibit ADAM22 translation.

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  • efficient adam22 surface expression is mediated by phosphorylation dependent interaction with 14 3 3 protein family members
    Journal of Cell Science, 2006
    Co-Authors: Nathan Godde, Giovanna M Dabaco, Lucy Paradiso, Ulrike Novak

    Abstract:

    ADAM22 is one of three catalytically inactive ADAM family members highly expressed in the brain. ADAM22 has numerous splice variants, all with considerable cytoplasmic tails of up to 148 amino acids. ADAM22 can act to inhibit cell proliferation, however, it has been suggested that it also acts as an adhesion protein. We identified three 14-3-3 protein members by a yeast two-hybrid screen and show by co-immunoprecipitation that the cytoplasmic domain of ADAM22 can interact with all six 14-3-3 proteins expressed in the brain. In addition, we show that 14-3-3 proteins interact preferentially with the serine phosphorylated precursor form of ADAM22. ADAM22 has two 14-3-3 protein binding consensus motifs; the first binding site, spanning residues 831-834, was shown to be the most crucial for 14-3-3 binding to occur. The interaction between ADAM22 and 14-3-3 proteins is dependent on phosphorylation of ADAM22, but not of 14-3-3 proteins. ADAM22 point mutants lacking functional 14-3-3 protein binding motifs could no longer accumulate efficiently at the cell surface. Deletion of both 14-3-3 binding sites and newly identified ER retention motifs restored localization of ADAM22 at the cell surface. These results reveal a role for 14-3-3 proteins in targeting ADAM22 to the membrane by masking ER retention signals.

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  • adam22 expressed in normal brain but not in high grade gliomas inhibits cellular proliferation via the disintegrin domain
    Neurosurgery, 2006
    Co-Authors: Giovanna M Dabaco, Nathan Godde, Lucy Paradiso, Ken Ng, Andrew H Kaye, Ulrike Novak

    Abstract:

    OBJECTIVE: To study the expression and function of the brain-specific proteinase deficient disintegrins, ADAM11 and ADAM22 (a disintegrin and metalloproteinase). METHODS: Specimens of low- and high-grade gliomas and normal brain were analyzed for ADAM11 and ADAM22 expression using Western blotting. The effects of overexpression of ADAM11 and ADAM22 in glioma cells on growth were analyzed using bromodeoxyuridine incorporation linked to immunocytochemistry. Similarly analyzed were the effects on cell proliferation of bacterially expressed glutathione S-transferase fusion proteins with the disintegrin domain of ADAM11 and ADAM22. RESULTS: ADAM22 is expressed in normal brain and some low-grade gliomas, but not in high-grade gliomas, whereas ADAM11 is expressed in all low- and high-grade gliomas. In vitro, ADAM22 inhibits cellular proliferation of glioma derived astrocytes. The growth inhibition appears to be mediated by interactions between the disintegrin domain of ADAM22 and specific integrins expressed on the cell surface. This growth inhibition can be avoided by over-expression of integrin linked kinase. CONCLUSION: ADAM22, a brain-specific cell surface protein, mediates growth inhibition using an integrin dependent pathway. It is expressed in normal brain but not in high-grade gliomas. A related protein, ADAM11, has only a minor effect on cell growth, and its expression is unchanged in low- and high-grade gliomas.

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