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54. Mmp14 is required for matrisome homeostasis and circadian rhythm in fibroblasts

Author

Ching-Yan Chloé Yeung, Richa Garva, Adam Pickard, Yinhui Lu, Venkatesh Mallikarjun, Joe Swift, Susan H. Taylor, Jyoti Rai, David R. Eyre, Mayank Chaturvedi, Yoshifumi Itoh, Qing-Jun Meng, Cornelia Mauch, Paola Zigrino, and Karl E. Kadler

Abstract

The circadian clock in tendon regulates the daily rhythmic synthesis of collagen-I and the appearance and disappearance of small-diameter collagen fibrils in the extracellular matrix. How the fibrils are assembled and removed is not fully understood. Here, we first showed that the collagenase, membrane type I-matrix metalloproteinase (MT1-MMP, encoded byMmp14), is regulated by the circadian clock in postnatal mouse tendon. Next, we generated tamoxifen-inducedCol1a2-Cre-ERT2::Mmp14KO mice (Mmp14conditional knockout (CKO)). The CKO mice developed hind limb dorsiflexion and thickened tendons, which accumulated narrow-diameter collagen fibrils causing ultrastructural disorganization. Mass spectrometry of control tendons identified 1195 proteins of which 212 showed time-dependent abundance. InMmp14CKO mice 19 proteins had reversed temporal abundance and 176 proteins lost time dependency. Among these, the collagen crosslinking enzymes lysyl oxidase-like 1 (LOXL1) and lysyl hydroxylase 1 (LH1; encoded byPlod2) were elevated and had lost time-dependent regulation. High-pressure chromatography confirmed elevated levels of hydroxylysine aldehyde (pyridinoline) crosslinking of collagen in CKO tendons. As a result, collagen-I was refractory to extraction. We also showed that CRISPR-Cas9 deletion ofMmp14from cultured fibroblasts resulted in loss of circadian clock rhythmicity of period 2 (PER2), and recombinant MT1-MMP was highly effective at cleaving soluble collagen-I but less effective at cleaving collagen pre-assembled into fibrils. In conclusion, our study shows that circadian clock-regulatedMmp14controls the rhythmic synthesis of small diameter collagen fibrils, regulates collagen crosslinking, and its absence disrupts the circadian clock and matrisome in tendon fibroblasts.

Published
2022
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55. XIAP promotes melanoma growth by inducing tumour neutrophil infiltration

Author

Mila Daoud, Pia Nora Broxtermann, Fabian Schorn, J Paul Werthenbach, Jens Michael Seeger, Lars M Schiffmann, Kerstin Brinkmann, Domagoj Vucic, Thomas Tüting, Cornelia Mauch, Dagmar Kulms, Paola Zigrino, and Hamid Kashkar

Subjects
Skin Neoplasms, Interleukin-8, Apoptosis, X-Linked Inhibitor of Apoptosis Protein, Biochemistry, Inhibitor of Apoptosis Proteins, Disease Models, Animal, Mice, Neutrophil Infiltration, Receptor-Interacting Protein Serine-Threonine Kinase 2, Genetics, Animals, Humans, Molecular Biology, Melanoma, Adaptor Proteins, Signal Transducing
Abstract

Elevated expression of the X-linked inhibitor of apoptosis protein (XIAP) has been frequently reported in malignant melanoma suggesting that XIAP renders apoptosis resistance and thereby supports melanoma progression. Independent of its anti-apoptotic function, XIAP mediates cellular inflammatory signalling and promotes immunity against bacterial infection. The pro-inflammatory function of XIAP has not yet been considered in cancer. By providing detailed in vitro analyses, utilising two independent mouse melanoma models and including human melanoma samples, we show here that XIAP is an important mediator of melanoma neutrophil infiltration. Neutrophils represent a major driver of melanoma progression and are increasingly considered as a valuable therapeutic target in solid cancer. Our data reveal that XIAP ubiquitylates RIPK2, involve TAB1/RIPK2 complex and induce the transcriptional up-regulation and secretion of chemokines such as IL8, that are responsible for intra-tumour neutrophil accumulation. Alteration of the XIAP-RIPK2-TAB1 inflammatory axis or the depletion of neutrophils in mice reduced melanoma growth. Our data shed new light on how XIAP contributes to tumour growth and provides important insights for novel XIAP targeting strategies in cancer.

Published
2022

57. XIAP promotes melanoma growth by inducing tumour neutrophil infiltration.

Author

Daoud, M, Broxtermann, PN, Schorn, F, Werthenbach, JP, Seeger, JM, Schiffmann, LM, Brinkmann, K, Vucic, D, Tüting, T, Mauch, C, Kulms, D, Zigrino, P, Kashkar, H, Daoud, M, Broxtermann, PN, Schorn, F, Werthenbach, JP, Seeger, JM, Schiffmann, LM, Brinkmann, K, Vucic, D, Tüting, T, Mauch, C, Kulms, D, Zigrino, P, and Kashkar, H

Abstract

Elevated expression of the X-linked inhibitor of apoptosis protein (XIAP) has been frequently reported in malignant melanoma suggesting that XIAP renders apoptosis resistance and thereby supports melanoma progression. Independent of its anti-apoptotic function, XIAP mediates cellular inflammatory signalling and promotes immunity against bacterial infection. The pro-inflammatory function of XIAP has not yet been considered in cancer. By providing detailed in vitro analyses, utilising two independent mouse melanoma models and including human melanoma samples, we show here that XIAP is an important mediator of melanoma neutrophil infiltration. Neutrophils represent a major driver of melanoma progression and are increasingly considered as a valuable therapeutic target in solid cancer. Our data reveal that XIAP ubiquitylates RIPK2, involve TAB1/RIPK2 complex and induce the transcriptional up-regulation and secretion of chemokines such as IL8, that are responsible for intra-tumour neutrophil accumulation. Alteration of the XIAP-RIPK2-TAB1 inflammatory axis or the depletion of neutrophils in mice reduced melanoma growth. Our data shed new light on how XIAP contributes to tumour growth and provides important insights for novel XIAP targeting strategies in cancer.

Published
2022

58. Loss of Endothelial Cell Matrix Metalloproteinase 14 Reduces Melanoma Growth and Metastasis by Increasing Tumor Vessel

Author

Kumper, Maike, Hessenthaler, Sabrina, Zamek, Jan, Niland, Stephan, Pach, Elke, Mauch, Cornelia, Zigrino, Paola, Kumper, Maike, Hessenthaler, Sabrina, Zamek, Jan, Niland, Stephan, Pach, Elke, Mauch, Cornelia, and Zigrino, Paola

Abstract

Matrix metalloproteinase (MMP) 14 belongs to a large family of zinc-dependent endopeptidases and plays a critical role in skin physiological and pathological processes. Complete loss of the protease resulted in severe developmental defects leading to early death. However, because of the premature death of the mice, the functional significance for endothelial cell (EC) expression of MMP14 in skin physiology and pathology in vivo after birth is yet unknown. Using a mouse model with constitutive EC-specific deletion of Mmp14 (Mmp14EC(-/-)), we showed that mice developed and bred normal, but melanoma growth and metastasis were reduced. Although vascularity was unaltered, vessel permeability was decreased. Deletion of MMP14 in ECs led to increased vessel coverage by pericytes and vascular endothelialecadherin expression in mice in vivo and in vitro but not in human ECs. Endothelial nitric oxide synthase expression and nitric oxide production were significantly reduced in Mmp14EC(-/-) ECs and MMP14-silenced human umbilical vein ECs. A direct correlation between endothelial nitric oxide synthase and MMP14 expression was detected in intratumoral vessels of human malignant melanomas. Altogether, we show that endothelial MMP14 controls tumor vessel function during melanoma growth. These data suggest that EC-derived MMP14 direct targeting alone or with vascular stabilizing agents may be therapeutically crucial in inhibiting melanoma growth and metastasis.

Published
2022

59. Role of MMP3 and fibroblast-MMP14 in skin homeostasis and repair

Author

Kuemper, Maike, Zamek, Jan, Steinkamp, Joy, Pach, Elke, Mauch, Cornelia, Zigrino, Paola, Kuemper, Maike, Zamek, Jan, Steinkamp, Joy, Pach, Elke, Mauch, Cornelia, and Zigrino, Paola

Abstract

Early lethality of mice with complete deletion of the matrix metalloproteinase MMP14 emphasized the proteases' pleiotropic functions. MMP14 deletion in adult dermal fibroblasts (MMP14Sf-/-) caused collagen type I accu-mulation and upregulation of MMP3 expression. To identify the compensatory role of MMP3, mice were generated with MMP3 deletion in addition to MMP14 loss in fibroblasts. These double deficient mice displayed a fibrotic phenotype in skin and tendons as detected in MMP14Sf-/-mice, but no additional obvious defects were detected. However, challenging the mice with full thickness excision wounds resulted in delayed closure of early wounds in the double deficient mice compared to wildtype and MMP14 single knockout controls. Over time wounds closed and epidermal integrity was restored. Interestingly, on day seven, post-wounding myofibroblast density was lower in the wounds of all knockout than in controls, they were higher on day 14. The delayed resolution of myofibroblasts from the granulation tissue is paralleled by reduced apoptosis of these cells, although proliferation of myofibroblasts is induced in the double deficient mice. Further analysis showed comparable TGF beta 1 and TGF beta R1 expression among all genotypes. In addition, in vitro, fibroblasts lacking MMP3 and MMP14 retained their ability to differentiate into myofibroblasts in response to TGF beta 1 treatment and me-chanical stress. However, in vivo, p-Smad2 was reduced in myofibroblasts at day 5 post-wounding, in double, but most significant in single knockout, indicating their involvement in TGF beta 1 activation. Thus, although MMP3 does not compensate for the lack of fibroblast-MMP14 in tissue homeostasis, simultaneous deletion of both proteases in fibroblasts delays wound closure during skin repair. Notably, single and double deficiency of these proteases modulates myofibroblast formation and resolution in wounds.

Published
2022

60. Metalloproteinases in dermal homeostasis

Author

Kuemper, Maike, Steinkamp, Joy, Zigrino, Paola, Kuemper, Maike, Steinkamp, Joy, and Zigrino, Paola

Abstract

Maintenance of skin homeostasis is a highly regulated and complex process involving a continuous remodeling by several extracellular matrix proteases, including metalloproteinases. The expression and activity of all metalloproteinases are under strict control, and their deregulation is often associated with diseases or chronic conditions, thereby being considered popular targets for developing new therapeutics. This review will highlight metalloproteinases of the MMP and ADAM families with functions in dermal homeostasis and give some insights into the mechanisms regulating their activity and expression. Furthermore, we discuss how the dysregulation of the most prominent family members affects dermal homeostasis by triggering disease development and influencing progression, focusing on cancer and aging. Here, recent discoveries and new approaches that target or exploit metalloproteinase activity in therapy are emphasized. The potential of naturally derived components in regulating metalloproteinase expression and activity in disease is discussed.

Published
2022

63. Mmp14 is required for matrisome homeostasis and circadian rhythm in fibroblasts

Author

Chloé Yeung, Ching-Yan, primary, Garva, Richa, additional, Pickard, Adam, additional, Lu, Yinhui, additional, Mallikarjun, Venkatesh, additional, Swift, Joe, additional, Taylor, Susan H., additional, Rai, Jyoti, additional, Eyre, David R., additional, Chaturvedi, Mayank, additional, Itoh, Yoshifumi, additional, Meng, Qing-Jun, additional, Mauch, Cornelia, additional, Zigrino, Paola, additional, and Kadler, Karl E., additional

Published
2022
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64. Matrix metalloproteinase 14 is required for fibrous tissue expansion

Author

Susan H Taylor, Ching-Yan Chloé Yeung, Nicholas S Kalson, Yinhui Lu, Paola Zigrino, Tobias Starborg, Stacey Warwood, David F Holmes, Elizabeth G Canty-Laird, Cornelia Mauch, and Karl E Kadler

Subjects
MT1-MMP, fibronectin, fibripositor, electron microscope, periostin, collagen, Medicine, Science, Biology (General), QH301-705.5
Abstract

Type I collagen-containing fibrils are major structural components of the extracellular matrix of vertebrate tissues, especially tendon, but how they are formed is not fully understood. MMP14 is a potent pericellular collagenase that can cleave type I collagen in vitro. In this study, we show that tendon development is arrested in Scleraxis-Cre::Mmp14 lox/lox mice that are unable to release collagen fibrils from plasma membrane fibripositors. In contrast to its role in collagen turnover in adult tissue, MMP14 promotes embryonic tissue formation by releasing collagen fibrils from the cell surface. Notably, the tendons grow to normal size and collagen fibril release from fibripositors occurs in Col-r/r mice that have a mutated collagen-I that is uncleavable by MMPs. Furthermore, fibronectin (not collagen-I) accumulates in the tendons of Mmp14-null mice. We propose a model for cell-regulated collagen fibril assembly during tendon development in which MMP14 cleaves a molecular bridge tethering collagen fibrils to the plasma membrane of fibripositors.

Published
2015
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70. Melanoma metastasis, BRAF mutation and GJB5 connexin expression: a new prognostic factor

Author

P Zigrino and J E Fromme

Subjects
Proto-Oncogene Proteins B-raf, Prognostic factor, Skin Neoplasms, business.industry, Melanoma, Connexin, Dermatology, medicine.disease, Prognosis, Connexins, Metastasis, Text mining, Mutation (genetic algorithm), Mutation, Cancer research, medicine, Humans, business
Abstract

Linked Article: Scatolini et al. Br J Dermatol 2022; 186:117–128.

Published
2021

75. Evaluations of insecticides to reduce transmission of Xylella fastidiosa in olives

Author

Vincenzo, Cavalieri, Fumarola, G., Zigrino, M., Di Carolo, M., Palmisano, F., Silletti, M.R., Palmisano, V., and Dongiovanni, C.

Subjects
olive quick decline syndrome, parasitic diseases, xylella, plant health, control
Abstract

The efficacy of several natural and synthetic compounds to suppress populations of Philaenus spumarius, the predominant EU vector of Xylella fastidiosa, has been investigated in the past recent years. As for many other vector-borne diseases, control strategies aim also to reduce the feeding events and therefore the chances of transmission. In this context, we evaluated the use of different compounds in reducing the rate of bacterial transmission in olives either under filed conditions or confined conditions in cages. In fields located in the infected area of Apulia (southern Italy), we tested the use of kaolin. Healthy plants were sprayed for three consecutive years on a calendar basis with kaolin and imidacloprid (control product). Results showed that neither kaolin or imidacloprid protected plants from infections, however for both treatments a delay in the progression of the infections (n. of infected plants) and symptom severity were recorded compared to the untreated control plants. When kaolin was applied in cages, results were similar in that number of infected plants was lower for the treated plants than for the untreated plants. In cage trials, compounds tested included imidacloprid, acetamiprid, delthametrin, and phosmet. Experiments conducted in cages were set up using Xylella-infected spittlebugs (apprx. 15% of qPCR-positive specimens). Insects were released in the cages after 3, 7 and 15 days after treatment (DAT) and maintained for 3 days for the inoculation access period. High mortality rates were recorded with all insecticides except for phosmet that showed inconsistent results. At 3 DAT, no infections were recorded on the seedlings sprayed with neonicotinoids and delthamethrin. Low or no infections were recorded with neonicotinoids and delthamethrin at 7 and 15 DAT, while rates of infections were similar for phosmet-sprayed and untreated controls.

Published
2021
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76. Fibroblast MMP14-Dependent Collagen Processing Is Necessary for Melanoma Growth

Author

Elke Pach, Jürgen Brinckmann, Cornelia Mauch, Matthias Rübsam, Maike Kümper, and Paola Zigrino

Subjects
0301 basic medicine, collagen, Cancer Research, Article, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, Dermis, medicine, melanoma, Fibroblast, RC254-282, Cell growth, Chemistry, Melanoma, MMP14, Proteolytic enzymes, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Oncology, Tumor progression, 030220 oncology & carcinogenesis, Cancer research, proteases
Abstract

Simple Summary Matrix metalloproteinases (MMPs) were considered as targets for the treatment of various cancers. However, initial trials using broad inhibitors to MMPs have failed, partly attributed to the contrasting functions of these proteases acting as tumor promoters and suppressors, among other reasons. Our data now suggest that specific inhibition of MMP14 might represent a more specific approach, as loss of this protease in fibroblasts resulted in reduced growth of grafted melanomas. Here, we found that deletion of MMP14 in fibroblasts generates a matrix-rich environment that reduces tumor vascularization and melanoma cell proliferation. In in vitro and ex vivo assays, we showed that the latter is mediated by stiffening of the tissue due to collagen accumulation. Additionally, in vivo, we show that independently of MMP14 deletion, a collagen-rich stiff matrix inhibits the growth of melanomas. Abstract Skin homeostasis results from balanced synthesis and degradation of the extracellular matrix in the dermis. Deletion of the proteolytic enzyme MMP14 in dermal fibroblasts (MMP14Sf−/−) leads to a fibrotic skin phenotype with the accumulation of collagen type I, resulting from impaired proteolysis. Here, we show that melanoma growth in these mouse fibrotic dermal samples was decreased, paralleled by reduced tumor cell proliferation and vessel density. Using atomic force microscopy, we found increased peritumoral matrix stiffness of early but not late melanomas in the absence of fibroblast-derived MMP14. However, total collagen levels were increased at late melanoma stages in MMP14Sf−/− mice compared to controls. In ex vivo invasion assays, melanoma cells formed smaller tumor islands in MMP14Sf−/− skin, indicating that MMP14-dependent matrix accumulation regulates tumor growth. In line with these data, in vitro melanoma cell growth was inhibited in high collagen 3D spheroids or stiff substrates. Most importantly, in vivo induction of fibrosis using bleomycin reduced melanoma tumor growth. In summary, we show that MMP14 expression in stromal fibroblasts regulates melanoma tumor progression by modifying the peritumoral matrix and point to collagen accumulation as a negative regulator of melanoma.

Published
2021

78. Treatment of spontaneously hypertensive rats with rosiglitazone ameliorates cardiovascular pathophysiology via antioxidant mechanisms in the vasculature

Author

Potenza, Maria A., Gagliardi, Sara, De Benedictis, Leonarda, Zigrino, Addolorata, Tiravanti, Edy, Colantuono, Giuseppe, Federici, Antonio, Lorusso, Loredana, Benagiano, Vincenzo, Quon, Michael J., and Montagnani, Monica

Subjects
Hypertension -- Care and treatment, Animal models in research -- Usage, Rosiglitazone maleate -- Usage, Rosiglitazone maleate -- Health aspects, Antioxidants -- Usage, Antioxidants -- Health aspects, Biological sciences
Abstract

Oxidative stress contributes to cardiovascular complications of diabetes, in part, by reducing the bioavailability of nitric oxide (NO). We investigated the mechanisms whereby the insulin sensitizer rosiglitazone may ameliorate oxidative stress in the vasculature of spontaneously hypertensive rats (SHR). Nine-week-old SHR were treated by gavage for 7 wk with rosiglitazone (5 mg x [kg.sup.-1] x [day.sup.-1]) or vehicle control. Treatment of SHR with rosiglitazone lowered systolic blood pressure, reduced fasting plasma insulin and asymmetrical dimethylarginine, and increased insulin sensitivity (when compared with vehicle treatment). In vessel homogenates and serum from rosiglitazone-treated SHR, SOD activity was enhanced, while 8-iso-[PGF.sub.2[alpha]], (lipid peroxidation product) was reduced (when compared with samples from vehicle-treated SHR). Moreover, expression of p22phox (catalytic subunit of NADPH oxidase) as well as nitrotyrosine and superoxide content were all reduced in the aortas of rosiglitazone-treated SHR. In mesenteric vascular beds (MVB) isolated ex vivo from rosiglitazone-treated SHR, NO-dependent vasodilator actions of insulin were improved when compared with MVB from vehicle-treated SHR. Acute pretreatment of MVB from vehicle-treated SHR with apocynin (NADPH oxidase inhibitor) enhanced vasodilator actions of insulin (results comparable to those in MVB from rosiglitazone-treated SHR). In Langendorff heart preparations from rosiglitazone-treated SHR, ischemia/reperfusion injury caused infarcts 40% smaller than in hearts from vehicle-treated SHR. Acute pretreatment of hearts from vehicle-treated SHR with apocynin produced similar results. Finally, rosiglitazone treatment of endothelial cells in primary culture reduced superoxide induced by insulin-resistant conditions. We conclude that rosiglitazone therapy in SHR increases SOD activity and decreases p22phox expression in the vasculature to reduce oxidant stress leading to an improved cardiovascular phenotype. oxidative stress

Published
2009

79. Inhibition of clathrin-mediated endocytosis by knockdown of AP-2 leads to alterations in the plasma membrane proteome

Author

David Tobys, Stefan Höning, Eva Cziudaj, Tobias Blaeske, Paola Zigrino, Peter Zentis, Lisa Maria Kowalski, Stefan Müller, and Elke Pach

Subjects
Proteome, Endosome, media_common.quotation_subject, Endocytic cycle, education, Biology, Endocytosis, Biochemistry, Clathrin, Structural Biology, Lysosome, ddc:570, Genetics, medicine, Internalization, Molecular Biology, media_common, Cell Membrane, Clathrin-Coated Vesicles, Cell Biology, Receptor-mediated endocytosis, Cell biology, medicine.anatomical_structure, Membrane protein, biology.protein
Abstract

In eukaryotic cells, clathrin-mediated endocytosis (CME) is a central pathway for the internalization of proteins from the cell surface, thereby contributing to the maintenance of the plasma membrane protein composition. A key component for the formation of endocytic clathrin-coated vesicles (CCVs) is AP-2, as it sequesters cargo membrane proteins, recruits a multitude of other endocytic factors and initiates clathrin polymerization. Here, we inhibited CME by depletion of AP-2 and explored the consequences for the plasma membrane proteome. Quantitative analysis revealed accumulation of major constituents of the endosomal-lysosomal system reflecting a block in retrieval by compensatory CME. The noticeable enrichment of integrins and blockage of their turnover resulted in severely impaired cell migration. Rare proteins such as the anti-cancer drug target CA9 and tumor markers (CD73, CD164, CD302) were significantly enriched. The AP-2 knockdown attenuated the global endocytic capacity, but clathrin-independent entry pathways were still operating, as indicated by persistent internalization of specific membrane-spanning and GPI-anchored receptors (PVR, IGF1R, CD55, TNAP). We hypothesize that blocking AP-2 function and thus inhibiting CME may be a novel approach to identify new druggable targets, or to increase their residence time at the plasma membrane, thereby increasing the probability for efficient therapeutic intervention. This article is protected by copyright. All rights reserved.

Published
2021

82. A Disintegrin and Metalloprotease (ADAM): Historical Overview of Their Functions

Author

Nives Giebeler and Paola Zigrino

Subjects
ADAM, disintegrin, SVMP, Medicine
Abstract

Since the discovery of the first disintegrin protein from snake venom and the following identification of a mammalian membrane-anchored metalloprotease-disintegrin implicated in fertilization, almost three decades of studies have identified additional members of these families and several biochemical mechanisms regulating their expression and activity in the cell. Most importantly, new in vivo functions have been recognized for these proteins including cell partitioning during development, modulation of inflammatory reactions, and development of cancers. In this review, we will overview the a disintegrin and metalloprotease (ADAM) family of proteases highlighting some of the major research achievements in the analysis of ADAMs’ function that have underscored the importance of these proteins in physiological and pathological processes over the years.

Published
2016
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84. Loss of ADAM9 Leads to Modifications of the Extracellular Matrix Modulating Tumor Growth

Author

Julia Fromme, Lavakumar Reddy Aramadhaka, Nives Giebeler, Jay W. Fox, Paola Zigrino, Elke Pach, Anna N. Abety, and Cornelia Mauch

Subjects
0301 basic medicine, Stromal cell, ADAM9, Decorin, extracellular matrix, collagen type I, lcsh:QR1-502, Biochemistry, Article, lcsh:Microbiology, Extracellular matrix, 03 medical and health sciences, Mice, 0302 clinical medicine, Dermis, Cell Line, Tumor, fibroblasts, Chlorocebus aethiops, Matrix Metalloproteinase 13, medicine, Matrix Metalloproteinase 14, melanoma, Animals, Fibroblast, Molecular Biology, Cell Proliferation, Tumor microenvironment, biology, Chemistry, Wild type, Membrane Proteins, Cell biology, Fibronectins, Fibronectin, ADAM Proteins, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, COS Cells, biology.protein, Collagen, Stromal Cells
Abstract

ADAM9 is a metalloproteinase strongly expressed at the tumor-stroma border by both tumor and stromal cells. We previously showed that the host deletion of ADAM9 leads to enhanced growth of grafted B16F1 melanoma cells by a mechanism mediated by TIMP1 and the TNF-&alpha, /sTNFR1 pathway. This study aimed to dissect the structural modifications in the tumor microenvironment due to the stromal expression of ADAM9 during melanoma progression. We performed proteomic analysis of peritumoral areas of ADAM9 deleted mice and identified the altered expression of several matrix proteins. These include decorin, collagen type XIV, fibronectin, and collagen type I. Analysis of these matrices in the matrix producing cells of the dermis, fibroblasts, showed that ADAM9&minus, /&minus, and wild type fibroblasts synthesize and secreted almost comparable amounts of decorin. Conversely, collagen type I expression was moderately, but not significantly, decreased at the transcriptional level, and the protein increased in ADAM9&minus, fibroblast mono- and co-cultures with melanoma media. We show here for the first time that ADAM9 can release a collagen fragment. Still, it is not able to degrade collagen type I. However, the deletion of ADAM9 in fibroblasts resulted in reduced MMP-13 and -14 expression that may account for the reduced processing of collagen type I. Altogether, the data show that the ablation of ADAM9 in the host leads to the altered expression of peritumoral extracellular matrix proteins that generate a more favorable environment for melanoma cell growth. These data underscore the suppressive role of stromal expression of ADAM9 in tumor growth and call for a better understanding of how protease activities function in a cellular context for improved targeting.

Published
2020

85. Fibroblast MMP14-Dependent Collagen Processing Is Necessary for Melanoma Growth

Author

Pach, Elke, Brinckmann, Juergen, Ruebsam, Matthias, Kuemper, Maike, Mauch, Cornelia, Zigrino, Paola, Pach, Elke, Brinckmann, Juergen, Ruebsam, Matthias, Kuemper, Maike, Mauch, Cornelia, and Zigrino, Paola

Abstract

Simple Summary Matrix metalloproteinases (MMPs) were considered as targets for the treatment of various cancers. However, initial trials using broad inhibitors to MMPs have failed, partly attributed to the contrasting functions of these proteases acting as tumor promoters and suppressors, among other reasons. Our data now suggest that specific inhibition of MMP14 might represent a more specific approach, as loss of this protease in fibroblasts resulted in reduced growth of grafted melanomas. Here, we found that deletion of MMP14 in fibroblasts generates a matrix-rich environment that reduces tumor vascularization and melanoma cell proliferation. In in vitro and ex vivo assays, we showed that the latter is mediated by stiffening of the tissue due to collagen accumulation. Additionally, in vivo, we show that independently of MMP14 deletion, a collagen-rich stiff matrix inhibits the growth of melanomas. Skin homeostasis results from balanced synthesis and degradation of the extracellular matrix in the dermis. Deletion of the proteolytic enzyme MMP14 in dermal fibroblasts (MMP14(Sf-/-)) leads to a fibrotic skin phenotype with the accumulation of collagen type I, resulting from impaired proteolysis. Here, we show that melanoma growth in these mouse fibrotic dermal samples was decreased, paralleled by reduced tumor cell proliferation and vessel density. Using atomic force microscopy, we found increased peritumoral matrix stiffness of early but not late melanomas in the absence of fibroblast-derived MMP14. However, total collagen levels were increased at late melanoma stages in MMP14(Sf-/-) mice compared to controls. In ex vivo invasion assays, melanoma cells formed smaller tumor islands in MMP14(Sf-/-) skin, indicating that MMP14-dependent matrix accumulation regulates tumor growth. In line with these data, in vitro melanoma cell growth was inhibited in high collagen 3D spheroids or stiff substrates. Most importantly, in vivo induction of fibrosis using bleomycin reduced

Published
2021

86. Extracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth

Author

Pach, Elke, Kuemper, Maike, Fromme, Julia E., Zamek, Jan, Metzen, Fabian, Koch, Manuel, Mauch, Cornelia, Zigrino, Paola, Pach, Elke, Kuemper, Maike, Fromme, Julia E., Zamek, Jan, Metzen, Fabian, Koch, Manuel, Mauch, Cornelia, and Zigrino, Paola

Abstract

Maintaining a balanced state in remodeling the extracellular matrix is crucial for tissue homeostasis, and this process is altered during skin cancer progression. In melanoma, several proteolytic enzymes are expressed in a time and compartmentalized manner to support tumor progression by generating a permissive environment. One of these proteases is the matrix metalloproteinase 14 (MMP14). We could previously show that deletion of MMP14 in dermal fibroblasts results in the generation of a fibrotic-like skin in which melanoma growth is impaired. That was primarily due to collagen I accumulation due to lack of the collagenolytic activity of MMP14. However, as well as collagen I processing, MMP14 can also process several extracellular matrices. We investigated extracellular matrix alterations occurring in the MMP14-deleted fibroblasts that can contribute to the modulation of melanoma growth. The matrix deposited by cultured MMP14-deleted fibroblast displayed an antiproliferative and anti-migratory effect on melanoma cells in vitro. Analysis of the secreted and deposited-decellularized fibroblast's matrix identified a few altered proteins, among which the most significantly changed was collagen XIV. This collagen was increased because of post-translational events, while de novo synthesis was unchanged. Collagen XIV as a substrate was not pro-proliferative, pro-migratory, or adhesive, suggesting a negative regulatory role on melanoma cells. Consistent with that, increasing collagen XIV concentration in wild-type fibroblast-matrix led to reduced melanoma proliferation, migration, and adhesion. In support of its anti-tumor activity, enhanced accumulation of collagen XIV was detected in peritumoral areas of melanoma grown in mice with the fibroblast's deletion of MMP14. In advanced human melanoma samples, we detected reduced expression of collagen XIV compared to benign nevi, which showed a robust expression of this molecule around melanocytic nests. This study shows that l

Published
2021

90. Phospholipidation of nuclear proteins by the human papillomavirus E6 oncoprotein: implication in carcinogenesis

Author

Birgid Markiefka, Baki Akgül, Martin Hufbauer, Britta Brügger, Timo Sachsenheimer, Slawomir Majewski, Paola Zigrino, and Benjamin L. Marx

Subjects
0301 basic medicine, Genetically modified mouse, SND1, skin cancer, E6 oncoprotein, Phosphatase, medicine.disease_cause, Cell biology, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, Oncology, Downregulation and upregulation, chemistry, medicine, OCRL, nuclear phosphatidylinositol-4,5-bisphosphate, Phosphatidylinositol, Nuclear protein, human papillomavirus, phosphatidylinositides, Carcinogenesis, Research Paper
Abstract

Phospholipids regulate numerous cellular functions and their deregulation is known to be associated with cancer development. Here, we show for the first time that expression of the E6 oncoprotein of human papillomavirus type 8 (HPV8) leads to a profound increase in nuclear phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) lipid levels in monolayer cultures, that led to an aberrant phospholipidation of cellular proteins. Elevated PI(4,5)P2 levels in organotypic skin cultures, skin tumors of K14-HPV8-E6 transgenic mice as well as HPV8 positive skin carcinomas highly suggest a decisive role of PI(4,5)P2 in HPV associated squamous-cell-carcinoma development. Furthermore, mass-spectrometric analysis confirmed an increase of PI(4,5)P2, which was characterized by a shift in the distribution of lipid species. PI(4,5)P2 upregulation was independent of E6 interference with MAML1. However, E6 does interfere with the PI(4,5)P2 metabolic pathway by upregulation of phosphatidylinositol-4-phosphate-5-kinase type I and phosphatidylinositol-5-phosphate 4-kinase type II as well as the binding to 5’-phosphatase OCRL and phosphatidylinositol. All of these mechanisms combined may contribute to PI(4,5)P2 elevation in E6 positive cells. The identification of CAND1 and SND1 – two proteins known to be involved in carcinogenic processes – were significantly stronger phospholipidized in the presence of E6. In conclusion we provide evidence that the modulation of the PI(4,5)P2 metabolism is a novel oncogenic mechanism relevant for HPV-induced carcinogenesis.

Published
2018
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93. ADAM9

Author

Zigrino, Paola, primary and Mauch, Cornelia, additional

Published
2013
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94. Contributors

Author

Abbott, Catherine Anne, primary, Abraham, Carmela R., additional, Adachi, Hideki, additional, Adachi, Osao, additional, Adam, Zach, additional, Adams, Michael W.W., additional, Adang, Michael J., additional, Adham, Ibrahim M., additional, Aducci, Patrizia, additional, Agard, David A., additional, Agranovsky, Alexey A., additional, Akamatsu, Tetsuya, additional, Akiyama, Yoshinori, additional, Albrechtsen, Reidar, additional, Alejo, Alí, additional, Amberg, Sean M., additional, Amerik, Alexander Y., additional, Amparyup, Piti, additional, Andrade, Felipe, additional, Andrés, Germán, additional, Andrews, Daniel M., additional, Andrews, Robert K., additional, Antalis, Toni M., additional, Anthony, Colin S., additional, Aoki, Naoya, additional, Apte, Suneel S., additional, Arima, Kazunari, additional, Arlaud, Gérard, additional, Arni, Raghuvir Krishnaswamy, additional, Arnoux, Pascal, additional, Aronson, Nathan N., additional, Arthur, Michel, additional, Asano, Yasuhisa, additional, Ascenzi, Paolo, additional, Assakura, Marina T., additional, Auld, David S., additional, Ávila, Veridiana de Melo Rodrigues, additional, Avilés, Francesc X., additional, Awad, William M., additional, Bachhawat, Anand K., additional, Bai, Shan, additional, Baird, Teaster T., additional, Bajaj, S. Paul, additional, Baker, Susan C., additional, Banbula, Agnieszka, additional, Barrett, Alan J., additional, Barrowman, Jemima, additional, Bartlett, John D., additional, Bartsch, Jörg W., additional, Baschuk, Nikola, additional, Baskova, Isolda P., additional, Batra, Jyotsna, additional, Bauer, Karl, additional, Baumann, Ulrich, additional, Baumeister, Wolfgang, additional, Bauvois, Cédric, additional, Bayés, Alex, additional, Beauvais, Anne, additional, Becker-Pauly, Christoph, additional, Begley, Tadhg P., additional, Békés, Miklós, additional, Belas, Robert, additional, Beleford, Daniah, additional, Beppu, Teruhiko, additional, Bergmann, Ernst M., additional, Bernard, Bruno A., additional, Bernard, Dominique, additional, Berndt, Michael C., additional, Berruti, Giovanna, additional, Berry, Colin, additional, Bertenshaw, Greg P., additional, Betzel, Christian, additional, Bhaskarla, Chetana, additional, Bhosale, Manoj, additional, Bierbaum, Gabriele, additional, Bjarnason Jón, B., additional, Blaber, Michael, additional, Blackman, Michael J., additional, Blinkovsky, Alexander, additional, Boeke, Jef D., additional, Bogyo, Matthew, additional, Bohn, Stefan, additional, Boileau, Guy, additional, Boland, Mike, additional, Bolken, Tové C., additional, Bond, Judith S., additional, Bondeson, Jan, additional, Bordallo, Javier, additional, Borelli, Claudia, additional, Botelho, Tiago O., additional, Bott, Richard R., additional, Bourne, David G., additional, Bovenschen, Niels, additional, Bradshaw, Ralph A., additional, Breddam, Klaus, additional, Brew, Keith, additional, Brindley, Paul J., additional, Brinkman, Diane L., additional, Britton, Collette, additional, Broadbent, Jeff R., additional, Broadhurst, Anne, additional, Brómme, Dieter, additional, Broom, Murray, additional, Brown, Jeremy S., additional, Brown, Mark A., additional, Bruchhaus, Iris, additional, Burleigh, Barbara A., additional, Burns, Kristin E., additional, Burrows, James F., additional, Butler, Michael J., additional, Buttle, David J., additional, Byrd, Chelsea M., additional, Byun, Tony, additional, Cadel, Sandrine, additional, Caffrey, Conor R., additional, Cal, Santiago, additional, Caldentey, Javier, additional, Candela, Thomas, additional, Capasso, Clemente, additional, Capriogilio, Daniel R., additional, Carginale, Vincenzo, additional, Carmona, Adriana Karaoglanovic, additional, Carruthers, Vern B., additional, Castellino, Francis J., additional, Catanese, Joseph J., additional, Caterson, Bruce, additional, Caughey, George H., additional, Cawley, Naimh X., additional, Cawston, Tim E., additional, Cazzulo, Juan José, additional, Chai, Jijie, additional, Chai, Karl X., additional, Chaim, Olga Meiri, additional, Chang, L.S., additional, Chao, Julie, additional, Chapot-Chartier, Marie-Pierre, additional, Charli, Jean-Louis, additional, Charlier, Paulette, additional, Chave, Karen J., additional, Chen, Jian-Min, additional, Chen, Jinq-May, additional, Chen, Li-Mei, additional, Chen, Ya-Wen, additional, Chen, Yu-Yen, additional, Chevrier, Bernard, additional, Chich, Jean-François, additional, Chien, Jeremy, additional, Chimalapati, Suneeta, additional, Cho, Ki Joon, additional, Choi, Kwan Yong, additional, Chuang, Woei-Jer, additional, Chung, Chin Ha, additional, Chung, Ivy Yeuk Wah, additional, Clamagirand, Christine, additional, Clark, Ian M., additional, Clarke, Adrian K., additional, Clarke, Nicola E., additional, Clarke, Steven Gerard, additional, Clauziat, Philippe, additional, Clements, Judith A., additional, Coffinier, Catherine, additional, Cohen, Paul, additional, Colige, Alain, additional, Collignon, Anne, additional, Colloms, Sean D., additional, Conzelmann, Andreas, additional, Coombs, Graham H., additional, Cooney, Jakki C., additional, Cooper, Jonathan B., additional, Cooper, Max D., additional, Copeland, Nikki A., additional, Cottrell, Graeme S., additional, Coyle, Joseph T., additional, Craik, Charles S., additional, Creemers, John W.M., additional, Cretu, Daniela, additional, Croce, Jenifer, additional, Cross, Keith J., additional, Cueva, Rosario, additional, Cui, Sheng, additional, Cunha, Luis, additional, Cutting, Simon, additional, d’Enfert, Christophe, additional, D’Orchymont, Hugues, additional, Dahlbäck, Björn, additional, Dai, Shujia, additional, Dalbey, Ross E., additional, Dalton, John P., additional, Dando, Pam M., additional, Daniel, R.M., additional, Danilov, Sergei M., additional, Davies, Donna E., additional, De Araujo, Heloisa S., additional, De los Santos, Teresa, additional, de Luca, Viviana, additional, De Meester, Ingrid, additional, de Oliveira, Ana Karina, additional, de Oliveira, Eduardo Brandt, additional, De Oliveira, Pedro Lagerblad, additional, de Vos, Sarah, additional, Declercq, Jeroen, additional, Declercq, Wim, additional, Deghmane, Ala-Eddine, additional, Dekker, Niek, additional, Del Prete, Sonia, additional, Del Rosal, Marina, additional, Delmas, Bernard, additional, DeLotto, Robert, additional, Demidyuk, Ilya V., additional, Denison, Mark R., additional, Deussing, Jan M., additional, Devi, Lakshmi A., additional, Diamandis, Eleftherios P., additional, Diaz, Isabel, additional, Díaz-Perales, Araceli, additional, Dijkstra, Bauke W., additional, Ding, Yan, additional, Dixon, Jack E., additional, Dodt, Johannes, additional, Dokland, Terje, additional, Dolenc, Iztok, additional, Dong, Ningzheng, additional, Dong, Tran Cat, additional, Dong, Ying, additional, Dongre, Mitesh, additional, Donovan, Mark, additional, Dore, Timothy M., additional, Dorstyn, Loretta, additional, Dou, Hong, additional, Dou, Zhicheng, additional, Dougall, Annette M., additional, Drag, Marcin, additional, Dudley, Edward G., additional, Dunn, Ben M., additional, Dupuy, Bruno, additional, Duque-Magalhāes, Maria Conceicāo, additional, Durá, M. Asunción, additional, Eeckhout, Yves, additional, Eijsink, Vincent, additional, Eisen, Arthur Z., additional, Eissa, Azza, additional, Eklund, Sandra, additional, Eletr, Ziad M., additional, Ellis, Vincent, additional, Engel, Wolfgang, additional, Erdös, Ervin G., additional, Escalante, Teresa, additional, Estell, David A., additional, Etscheid, Michael, additional, Evans, Herbert J., additional, Everett, Roger D., additional, Faesen, Alex C., additional, Fahrenholz, Falk, additional, Fanjul-Fernández, Miriam, additional, Farady, Christopher J., additional, Feller, Georges, additional, Feng, Hong, additional, Fenster, Kurt M., additional, Férec, Claude, additional, Ferrari, Silvia, additional, Fingleton, Barbara, additional, Fisher, Jed F., additional, Fives-Taylor, Paula M., additional, Fong, Loren G., additional, Forneris, F., additional, Forster, Brian M., additional, Forster, Friedrich, additional, Foster, Simon J., additional, Foulon, Thierry, additional, Foundling, Stephen I., additional, Fox, Jay William, additional, Franzetti, Bruno, additional, Frasch, Alejandra P., additional, Freeze, Hudson H., additional, Frère, Jean-Marie, additional, Frey, Teryl K., additional, Fricke, Beate, additional, Fricker, Lloyd D., additional, Fridman, Rafael, additional, Froelich, Christopher J., additional, Fröhlich, Camilla, additional, Fu, Hsueh-Liang, additional, Fuhrmann, Cynthia N., additional, Fujimura, Satoshi, additional, Fujiwara, Hiroshi, additional, Fukushima, Jun, additional, Fukuyama, Keiichi, additional, Fuller, Robert S., additional, Fusek, Martin, additional, Gaboriaud, Christine, additional, Gache, Christian, additional, Gakh, Oleksandr, additional, Gal, Peter, additional, Gao, Junjun, additional, García-Sastre, Adolfo, additional, Gardiner, Donald L., additional, Gatehouse, John A., additional, Gaucher, G.M., additional, Gauthier, Francis, additional, Ghuysen, Jean-Marie, additional, Gibson, Wade, additional, Gillies, Jennifer, additional, Glaser, Elzbieta, additional, Glaser, Fabian, additional, Glickman, Michael H., additional, Goettig, Peter, additional, Goffin, Colette, additional, Gohda, Eiichi, additional, Goldberg, Alfred L., additional, Goldberg, Daniel E., additional, Goldberg, Gregory I., additional, Goldfarb, Nathan E., additional, Gomis-Rüth, F. Xavier, additional, Gopal, B., additional, Gorbalenya, Alexander E., additional, Gordon, Stuart G., additional, Gorrell, Mark D., additional, Götz, Friedrich, additional, Goulas, Theodoros, additional, Gouzy-Darmon, Cécile, additional, Govind, K., additional, Gráf, Lászlo, additional, Granados, Robert R., additional, Gräwert, Melissa Ann, additional, Gray, Douglas A., additional, Graycar, Thomas P., additional, Green, Jonathan A., additional, Gremski, Luiza Helena, additional, Groll, Michael, additional, Gromova, Tania Yu, additional, Gros, P., additional, Grubman, Marvin J., additional, Grunden, Amy M., additional, Gudmundsdóttir, Ágústa, additional, Guinand, Micheline, additional, Gully, Djamel, additional, Gustchina, Alla, additional, Gutiérrez, José María, additional, Ha, Byung Hak, additional, Haeggström, Jesper Z., additional, Hageman, James H., additional, Haiko, Johanna, additional, Hailfinger, Stephan, additional, Haitchi, Hans Michael, additional, Han, Ji Seon, additional, Hanquez, Chantal, additional, Harada, Minoru, additional, Hara-Nishimura, Ikuko, additional, Harboe, Marianne, additional, Härd, Torleif, additional, Harris, David A., additional, Hassiepen, Ulrich, additional, Hata, Shoji, additional, Hattori, Akira, additional, He, Rong-Qiao, additional, Heck, Albert J.R., additional, Hendricks, Dirk F., additional, Henrich, Bernhard, additional, Henriet, Patrick, additional, Hernández-Arana, Andrés, additional, Herrera-Camacho, Irma, additional, Heussipp, Gerhard, additional, Hibino, Toshihiko, additional, Hicks, P.M., additional, Hillman, Bradley I., additional, Hiraoka, B. Yukihiro, additional, Hiratake, Jun, additional, Hizukuri, Yohei, additional, Ho, Heng-Chien, additional, Hoa, Ngo Thi, additional, Hochstrasser, Mark, additional, Hodge, Kathryn M., additional, Hofmann, Theo, additional, Hohn, Thomas, additional, Hoidal, John R., additional, Höltje, Joachim-Volker, additional, Homma, Koichi J., additional, Honek, John F., additional, Hook, Vivian Y.H., additional, Hooper, John D., additional, Hooper, Nigel M., additional, Hosoi, Kazuo, additional, Howe, Christopher J., additional, Hruby, Dennis E., additional, Hseih, James J.-D., additional, Hsu, Chun-Chieh, additional, Huang, Tony T., additional, Huang, Tur-Fu, additional, Huet, Yoann, additional, Hughes, Clare, additional, Hugonnet, Jean-Emmanuel, additional, Huston, Adrienne L., additional, Ibrahim-Granet, Oumaïma, additional, Ichishima, Eiji, additional, Ikehara, Yukio, additional, Inagami, Tadashi, additional, Ingram, Jessica, additional, Isaac, R.E., additional, Isaya, Grazia, additional, Isaza, Clara E., additional, Ishii, Shin-ichi, additional, Isnard, Amandine, additional, Ito, Kiyoshi, additional, Ito, Koreaki, additional, Itoh, Yoshifumi, additional, Iturrioz, Xavier, additional, Iwanaga, Sadaaki, additional, Jack, Ralph W., additional, Jackson, Mel C., additional, James, Michael N.G., additional, Janata, Jiří, additional, Janoir, Claire, additional, Janska, Hanna, additional, Jarrell, Ken F., additional, Jaskolski, Mariusz, additional, Jaswal, Sheila S., additional, Jean, Ying Y., additional, Jenne, Dieter E., additional, Jeon, Young Joo, additional, Jiang, Ping, additional, Johnson, John E., additional, Johnson, Michael D., additional, Johnston, James A., additional, Jones, Amanda, additional, Jones, Elizabeth W., additional, Joudiou, Carine, additional, Juliano, Luiz, additional, Jung, Hea-Jin, additional, Jupp, Ray, additional, Kagawa, Todd F., additional, Kalbacher, Hubert, additional, Kamata, Yayoi, additional, Kaminogawa, Shuichi, additional, Kamio, Yoshiyuki, additional, Kaneda, Makoto, additional, Kang, Sung Gyun, additional, Kang, Sung Hwan, additional, Kania, Mary, additional, Kantyka, Tomasz, additional, Kanzawa, Nobuyuki, additional, Karim, Abdulkarim Y., additional, Kasumi, Takafumi, additional, Kataoka, Hiroaki, additional, Kaur, Hardeep, additional, Kawabata, Shun-Ichiro, additional, Kawaguchi, Mari, additional, Kay, John, additional, Kaynar, Murat, additional, Keiler, Kenneth C., additional, Kelly, R.M., additional, Kenton, Nathaniel T., additional, Kerr, Michael A., additional, Kersse, Kristof, additional, Kervinen, Jukka, additional, Kessler, Benedikt M., additional, Kessler, Efrat, additional, Khoronen, Timo K., additional, Kidd, Simon, additional, Kikkert, Marjolein, additional, Kilian, Mogens, additional, Kim, Do-Hyung, additional, Kim, Doyoun, additional, Kim, Eunice EunKyeong, additional, Kim, In Seop, additional, Kim, Jung-Gun, additional, Kim, Kyeong Kyu, additional, Kim, Kyung Hyun, additional, Kimber, Matthew S., additional, Kimura, Yukio, additional, Kirschke, Heidrun, additional, Kiso, Yoshiaki, additional, Kleanthous, Colin, additional, Klein, Jürgen R., additional, Klemba, Michael, additional, Kmiec, Beata, additional, Kobayashi, Hideyuki, additional, Kodama, Hiroyuki, additional, Koelsch, Gerald, additional, Kok, Jan, additional, Kolattukody, P.E., additional, Kolb, Fabrice A., additional, Kolmar, Harald, additional, Komori, Yumiko, additional, Konvalinka, Jan, additional, Korkmaz, Brice, additional, Kostrov, Sergey V., additional, Kräusslich, Hans-Georg, additional, Krczal, Gabi, additional, Kress, Lawrence F., additional, Kristjánsson, Magnüs Már, additional, Kučera, Tomáš, additional, Kukday, Sayali S., additional, Kumagai, Hidehiko, additional, Kumar, Sharad, additional, Kumarasiri, Malika, additional, Kumazaki, Takashi, additional, Kümmerer, Beate M., additional, Kuno, Kouji, additional, Kurkinen, Markku, additional, Kutejová, Eva, additional, Kveiborg, Marie, additional, Kwarciak, Agnieszka, additional, Laakkonen, Liisa, additional, Labrou, Nikolaos E., additional, Laing, Gavin D., additional, Lamppa, Gayle, additional, Langer, Thomas, additional, Laursen, Richard A., additional, Lawrenson, Richard A., additional, Layne, Matthew D., additional, Le Bonniec, Bernard F., additional, Leal, María C., additional, Lechan, Ronald M., additional, Lee, David H., additional, Lee, Irene, additional, Lee, Jae, additional, Lee, Kye Joon, additional, Lee, Soohee, additional, Lei, Xiaobo, additional, Leis, Jonathan, additional, LeMosy, Ellen K., additional, Lepage, Thierry, additional, Leppla, Stephen H., additional, Lesner, Adam, additional, Lessard, Ivan A.D., additional, Lhomond, Guy, additional, Li, Huilin, additional, Li, Shu-Ming, additional, Li, Weiguo, additional, Liao, Ta-Hsiu, additional, Liddington, Robert C., additional, Lieber, Toby, additional, Lijnen, H.R., additional, Lima, Christopher D., additional, Lin, Chen-Yong, additional, Lin, Gang, additional, Lin, Ming T., additional, Lin, Xinli, additional, Lin, Yee-Shin, additional, Lindsay, L.L., additional, Lipscomb, William N., additional, Little, John W., additional, Liu, Ching-Chuan, additional, Liu, Chuan-ju, additional, Lively, Mark O., additional, Livnat-Levanon, Nurit, additional, Ljungdahl, Per O., additional, Llorens-Cortes, Catherine, additional, Lobel, Peter, additional, Loh, Y. Peng, additional, Lohi, Jouko, additional, Lomonossoff, G.P., additional, Looze, Yvan, additional, López-Otin, Carlos, additional, Lopez-Quezada, Landys, additional, Loukas, Alex, additional, Lu, Long-Sheng, additional, Lundwall, Áke, additional, Luo, Liu-Ying, additional, Lupas, Andrei, additional, Luthe, Dawn S., additional, Lynch, Nicholas J., additional, Lyons, Peter J., additional, MacKay, Vivian L., additional, Macleod, Jesica M. Levingston, additional, Magdolen, Viktor, additional, Mainardi, Jean-Luc, additional, Mäkinen, Kauko K., additional, Mallari, Jeremy P., additional, Manandhar, Surya P., additional, Mandelbaum, Fajga R., additional, Manicone, Anne M., additional, Mansfeld, Johanna, additional, Marcotrigiano, Joseph, additional, Mares, Michael, additional, Marfany, Gemma, additional, Markland, Francis S., additional, Marokházi, Judith, additional, Marquis, Hélène, additional, Marr, Robert A., additional, Martegani, Enzo, additional, Martin, Erik W., additional, Martinez, Manuel, additional, Martins, L. Miguel, additional, Maruyama, Masato, additional, Maruyama, Masugi, additional, Maruyama, Sususmu, additional, Masaki, Takeharu, additional, Massoumi, Ramin, additional, Mathew, Rency T., additional, Matrisian, Lynn M., additional, Matsuda, Yoshihiro, additional, Matsushita, Osamu, additional, Matuschek, Marco, additional, Matušková, Anna, additional, Matúz, Krisztina, additional, Mauch, Cornelia, additional, Maurizi, Michael R., additional, Mayr, Lorenz M., additional, McCafferty, Dewey G., additional, McDonald, J. Ken, additional, McKerrow, James H., additional, McMillan, David, additional, Mecham, Robert P., additional, Mehta, Darshini P., additional, Meisinger, Chris, additional, Mellors, Alan, additional, Melton, Roger G., additional, Melvin, Jeffrey A., additional, Ménard, Robert, additional, Menéndez-Arias, Luis, additional, Menezes, Milene C., additional, Mesecar, Andrew, additional, Mesnage, Stéphane, additional, Meyer, Diane H., additional, Meyers, Gregor, additional, Michaelis, Susan, additional, Michalska, Karolina, additional, Mielicki, Wojciech P., additional, Mierau, Igor, additional, Mikoulinskaia, Galina V., additional, Miller, Charles G., additional, Miller, Lydia K., additional, Mills, John, additional, Mills, Kenneth V., additional, Min, Jinrong, additional, Mistou, Michel-Yves, additional, Misumi, Yoshio, additional, Miyoshi, Shin-ichi, additional, Mizutani, Shigehiko, additional, Mobashery, Shahriar, additional, Mochizuki, Satsuki, additional, Mock, William L., additional, Möhrlen, Frank, additional, Moiré, Nathalie, additional, Monahan, Paul E., additional, Moncada-Pazos, Angela, additional, Monnet, Véronique, additional, Monod, Michel, additional, Montecucco, Cesare, additional, Morelli, Laura, additional, Mori, Sumiko, additional, Morita, Takashi, additional, Morrissey, James H., additional, Morse, Richard J., additional, Mort, John S., additional, Mortensen, Uffe H., additional, Morty, Rory E., additional, Moss, Joel, additional, Motoshima, Hidemasa, additional, Mottram, Jeremy C., additional, Moura-da-Silva, Ana M., additional, Mudgett, Mary Beth, additional, Mundt, Egbert, additional, Murakami, Kazuo, additional, Murakami, Mario Tyago, additional, MurakamiMurofoshi, Kimiko, additional, Murao, Sawao, additional, Murphy, Gillian, additional, Murthy, M.R.N., additional, Muta, Tatsushi, additional, Myburgh, Elmarie, additional, Mzhavia, Nino, additional, Nabi, A.H.M. Nurun, additional, Nagase, Hideaki, additional, Nagle, Michael W., additional, Nägler, Dorit K., additional, Naik, Rajesh R., additional, Nair, Divya B., additional, Nakai, Toshiki, additional, Nakajima, Yoshitaka, additional, Nakamura, Yukio, additional, Nakatogawa, Hitoshi, additional, Nakayama, Toru, additional, Nalivaeva, Natalia N., additional, Nandi, Dipankar, additional, Nascimento-Silva, Maria Clara Leal, additional, Nasmyth, Kim, additional, Nathan, Carl F., additional, Navarro-García, Fernando, additional, Naves, Dayane Lorena, additional, Nedialkova, Danny D., additional, Neuman, Keir C., additional, Nguyen, Jeffrey-Tri, additional, Nguyen, Ky-Anh, additional, Niemirowicz, Gabriela T., additional, Nikai, Toshiaki, additional, Nishi, Eiichiro, additional, Nishii, Wataru, additional, Nishiyama, Makoto, additional, Nishiyama, Yasuhiro, additional, Noda, Masatoshi, additional, Nomura, Seiji, additional, Norioka, Shigemi, additional, Nsangou, Desire M.M., additional, O’Brien, Amornrat, additional, O’Connor, Michael B., additional, Oda, Kohei, additional, Odinokova, Irina V., additional, Oetjen, Joyce, additional, Ogura, Teru, additional, Ohman, Dennis E, additional, Ohsumi, Yoshinori, additional, Ojha, Mukti, additional, Okabe, Akinobu, additional, Okada, Yasunori, additional, Okamoto, Keinosuke, additional, Okuda, Kenji, additional, Okumura, Nobuaki, additional, Okuno, Takashi, additional, Oleson, Kjeld, additional, Oliveira de Giuseppe, Priscila, additional, Olivier, Martin, additional, Ono, Yasuko, additional, Oroszlan, Stephen, additional, Ota, Nobuyuki, additional, Ovadia, Michael, additional, O-Wang, Jiyang, additional, Oxvig, Claus, additional, Packer, Jeremy C.L., additional, Padilla-López, Sergio, additional, Paetzel, Mark, additional, Page, Michael J., additional, Page-McCaw, Andrea, additional, Paine, Mark J.I., additional, Park, Byoung Chul, additional, Park, Eunyong, additional, Park, John E., additional, Park, Pyong Woo, additional, Park, Sung Goo, additional, Parkin, Kirk L., additional, Parks, William C, additional, Paschoalin, Thaysa, additional, Pastore, Annalisa, additional, Patananan, Alexander Nikolich, additional, Paul, Sudhir, additional, Paulson, Henry L., additional, Pawel-Rammingen, Ulrich von, additional, Pearce, David A., additional, Pearson, Mark S., additional, Pei, Duanqing, additional, Pejler, Gunnar, additional, Pemberton, Alan D., additional, Peng, Jianhao, additional, Pernier, Julien, additional, Peters, Jan-Michael, additional, Pfirrmann, Thorsten, additional, Pham, Viet-Laï, additional, Pichová, Iva, additional, Pickering, Darren, additional, Piesse, Christophe, additional, Pignol, David, additional, Pike, Robert N., additional, Pinck, Lothaire, additional, Pirkle, Hubert, additional, Pitot, Henry C., additional, Plaut, Andrew G., additional, Ploegh, Hidde, additional, Polgár, László, additional, Porter, Corrine, additional, Postina, Rolf, additional, Potempa, Jan, additional, Poulsen, Knud, additional, Power, Scott D., additional, Pratt, Rex. F., additional, Prehna, Gerd, additional, Prévost, Gilles, additional, Pshezhetsky, Alexey V., additional, Qasim, Mohammad A., additional, Qian, Feng, additional, Qiu, Jiazhou, additional, Quesada, Víctor, additional, Radisky, Evette S., additional, Rader, Stephen D., additional, Raman, Kavita, additional, Ramsay, Andrew J., additional, Rancourt, Derrick E., additional, Ranjit, Najju, additional, Rao, Narayanam V., additional, Ratia, Kiira, additional, Rawlings, Neil D., additional, Rawson, Robert B., additional, Reddy, Vijay, additional, Redman, Colvin M., additional, Regonesi, Maria Elena, additional, Reichert, Andreas S., additional, Reichl, Antonia P., additional, Remaut, Han, additional, Remington, S. James, additional, Renatus, Martin, additional, Reverter, David, additional, Reynolds, Eric C., additional, Rholam, Mohamed, additional, Rice, Charles M., additional, Ridky, Todd W., additional, Riezman, Howard, additional, Rijken, D.C., additional, Rio, Marie-Christine, additional, Ritchie, Alison, additional, Robert-Baudouy, Janine, additional, Robinson, Mark W., additional, Robinson, Michael, additional, Rodriguez-Romero, Adela, additional, Rodriques, Renata Santos, additional, Rogers, John C., additional, Rojas, Camilo, additional, Romesberg, Floyd E., additional, Roper, David J., additional, Rosas-Murrieta, Nora, additional, Rose, A.M., additional, Rosenthal, Philip J., additional, Rosing, J., additional, Rossetto, Ornella, additional, Rossi, Véronique, additional, Roth, Richard A., additional, Rottensteiner, Hanspeter, additional, Rowan, Andrew D., additional, Rozanov, Mikhail, additional, Rucavado, Alexandra, additional, Ruecker, Andrea, additional, Rul, Françoise, additional, Rümenapf, Till, additional, Russo, Ilaria, additional, Ryan, Martin D., additional, Sacco, Elena, additional, Sadler, J. Evan, additional, Saenger, W., additional, Sahl, Hans-Georg, additional, Sajid, Mohammed, additional, Sakaguchi, Masayoshi, additional, Sakiyama, Fumio, additional, Salas, Maria L., additional, Salgado, Maria Cristina O., additional, Salvesen, Guy S., additional, Sánchez, Edith, additional, Sanchez, Eladio F., additional, Sang, Qing-Xiang Amy, additional, Sankaran, Krishnan, additional, Sarkar, Susanta K., additional, Sarras, Michael P., additional, Sasagawa, Yoshikiyo, additional, Satohiko, Araki, additional, Sauvage, Eric, additional, Saveanu, Loredana, additional, Savithri, H.S., additional, Sawada, Hitoshi, additional, Sawers, R. Gary, additional, Scarisbrick, Isobel A., additional, Schaller, Andreas, additional, Scheer, Justin M., additional, Scheiflinger, Friedrich, additional, Schiene-Fischer, Cordelia, additional, Schlomann, Uwe, additional, Schlösser, Manfred, additional, Schmaier, Alvin H., additional, Schmidt, Walter K., additional, Schneemann, Anette, additional, Schnellmann, Rick G., additional, Scholze, Henning, additional, Schomburg, Lutz, additional, Schwaeble, Wilhelm J., additional, Scott, Christopher J., additional, Scudiero, Rosaria, additional, Sehara-Fujisawa, Atsuko, additional, Seidah, Nabil G., additional, Seiki, Motoharu, additional, Sekiguchi, Junichi, additional, Senff-Ribeiro, Andrea, additional, Seong, Ihn Sik, additional, Serpe, Mihaela, additional, Serrano, Solange M.T., additional, Setlow, Peter, additional, Shahian, Tina, additional, Shanks, M., additional, Shao, Feng, additional, Shapiro, Steven D., additional, Sharma, Navneet, additional, Shaw, Lindsey N., additional, Shen, Aimee, additional, Shen, Lei, additional, Sherwood, Roger F., additional, Shi, Yun-Bo, additional, Shimoi, Hitoshi, additional, Shimura, Yoichiro, additional, Shirras, A.D., additional, Shridhar, Viji, additional, Shukla, Jinal K., additional, Siigur, Ene, additional, Siigur, Jüri, additional, Silmon de Monerri, Natalie C., additional, Sim, Robert B., additional, Simmer, James P., additional, Simmons, William H., additional, Singh, Jaspreet, additional, Singleton, Alison, additional, Sirakova, Tatiana D., additional, Sixma, Titia K., additional, Skern, Tim, additional, Skidgel, Randal A., additional, Slack, Jeffrey, additional, Sleat, David E., additional, Slusher, Barbara S., additional, Smith, Janet L., additional, Smith, Matthew A., additional, Smyth, Mark J., additional, Snijder, Erik J., additional, Sobhanifar, Solmaz, additional, Söderhaäll, Kenneth, additional, Sohar, Istvan, additional, Sonderegger, Peter, additional, Sorgine, Marcos Henrique Ferreira, additional, Sorimachi, 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2013
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