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Matrix Metalloproteinases
Gordon Research Conference

Rediscovering Metalloproteinases as Disease Targets

Dates

July 9-14, 2017

Location

University of New England
Biddeford, ME

Organizers

Chair:
Howard C. Crawford

Vice Chair:
Rama Khokha

Meeting Description

Since their discovery as tissue remodeling enzymes over 50 years ago, the matrix metalloproteinases (MMPs) and the related ADAM and ADAMTS families have been identified as major contributors to human diseases, ranging from inflammatory diseases to neurodegeneration to cancer. Once viewed monolithically as bad actors in disease progression, they were collectively thought to be an ideal drug target, especially to prevent tumor invasion and metastasis or to block tissue destruction in chronic inflammatory conditions. However, early clinical trials with metalloproteinase inhibitors were unsuccessful for a number of likely reasons, the most prominent being a lack of appreciation for the more nuanced functions of individual metalloproteinases. Indeed, while some metalloproteinases may promote disease processes, we now understand that others act to protect against disease morbidity, facilitate repair, dampen inflammation, and support other beneficial functions, contraindicating the use of broad-spectrum inhibitors. Hence, a common goal in the field has been to discover specific functions of specific MMPs and how their activities and substrate interactions are controlled, with the aim of identifying specific deleterious activities that can be targeted with new, rational therapies. The aim of this GRC is to highlight the investigative advances dissecting both the good and bad functions of individual MMPs and the many ways their activities are controlled by endogenous mechanisms. Discussions will explore new directions for investigations and highlight how these fundamental discoveries can lead to the design of novel, specific metalloproteinase-targeted modulators for the treatment of human disease.

Related Meeting

This GRC was held in conjunction with the "Matrix Metalloproteinases" Gordon Research Seminar (GRS). Refer to the associated GRS program page for more information.

Contributors

Meeting Program

Sunday
2:00 pm - 9:00 pmArrival and Check-in
6:00 pmDinner
7:30 pm - 7:40 pmWelcome / Introductory Comments by GRC Site Staff
7:40 pm - 9:30 pmKeynote Session: Metalloproteinases in the Clinic
Discussion Leader: Barbara Fingleton (Vanderbilt University, USA)
7:40 pm - 8:20 pmIrit Sagi (Weizmann Institute of Science, Israel)
"The Comeback of MMPs in Therapy"
8:20 pm - 8:30 pmDiscussion
8:30 pm - 8:50 pmVictoria Smith (Gilead Sciences, USA)
"Making the Case for GS-5745, an Anti-MMP9 Antibody Currently in Cancer Clinical Trials"
8:50 pm - 8:55 pmDiscussion
8:55 pm - 9:15 pmNoopur Raje (Harvard Medical School, USA)
"Rehabilitating a Lost Drug - The Story of Thalidomide"
9:15 pm - 9:20 pmDiscussion
9:20 pm - 9:30 pmGeneral Discussion
Monday
7:30 am - 8:30 amBreakfast
9:00 am - 12:30 pmMetalloproteinases in Tissue Remodeling
Session in memory of Dr. Roger Tsien.
Discussion Leader: Suneel Apte (Cleveland Clinic, USA)
9:00 am - 9:10 amIntroduction by Discussion Leader
9:10 am - 9:25 amStephen Adams (University of California, San Diego, USA)
"Protease-Triggered Cancer Imaging and Therapy"
9:25 am - 9:30 amDiscussion
9:30 am - 9:45 amVarda Lev-Ram (University of California, San Diego, USA)
"Could Life-Long Memory Be Encoded in the Pattern of Holes in the Perineuronal Net?"
9:45 am - 9:50 amDiscussion
9:50 am - 10:00 amDina Hingorani (Howard Hughes Medical Institute, USA)
"Using an MMP-Cleavable Fluorescently Labeled Ratiometric Activatable Cell Penetrating Peptide (RACPP) for the Early Detection of Oral Cancer"
10:00 am - 10:05 amDiscussion
10:05 am - 10:25 amCoffee Break
10:25 am - 10:45 amBi-Sen Ding (Weill Cornell Medicine, USA)
"Regulation of Organ Regeneration and Fibrosis by Vascular-Derived MMPs"
10:45 am - 10:55 amDiscussion
10:55 am - 11:15 amStefan Lichtenthaler (Technical University of Munich, Germany)
"ADAM10 Substrates and Functions in Axon Targeting and Myelenation"
11:15 am - 11:25 amDiscussion
11:25 am - 11:45 amSantiago Rivera (Aix-Marseille University / CNRS, France)
"MT-MMPs, New Actors and Potential Targets in Alzheimer's Disease"
11:45 am - 11:55 amDiscussion
11:55 am - 12:05 pmMitsuharu Hattori (Nagoya City University, Japan)
"ADAMTS-3 Inactivates Reelin, an Important Regulator of Brain Development and Function"
12:05 pm - 12:10 pmDiscussion
12:10 pm - 12:20 pmSean Gill (Western University, Canada)
"The Role of Tissue Inhibitors of Metalloproteinases in Pulmonary Microvascular Endothelial Cell Barrier Dysfunction During Sepsis"
12:20 pm - 12:25 pmDiscussion
12:25 pm - 12:30 pmGeneral Discussion
12:30 pmLunch
1:30 pm - 4:00 pmFree Time
3:00 pm - 4:00 pmPower Hour
The GRC Power Hour is an optional informal gathering open to all meeting participants. It is designed to help address the challenges women face in science and support the professional growth of women in our communities by providing an open forum for discussion and mentoring.
Organizer: Rama Khokha (Princess Margaret Cancer Centre, Canada)
4:00 pm - 6:00 pmPoster Session
6:00 pmDinner
7:30 pm - 9:30 pmBeyond the Catalytic Site: Endogenous Regulation of ADAM Activity
Discussion Leader: Carl Blobel (Hospital for Special Surgery, Weill Cornell Medicine, USA)
7:30 pm - 7:40 pmIntroduction by Discussion Leader
7:40 pm - 8:00 pmMatthew Freeman (University of Oxford, United Kingdom)
"Molecular Mechanisms and Biological Roles of iRhom/ADAM17 Signaling"
8:00 pm - 8:10 pmDiscussion
8:10 pm - 8:30 pmMichael Tomlinson (University of Birmingham, United Kingdom)
"Regulation of ADAM10 by Tetraspanins"
8:30 pm - 8:40 pmDiscussion
8:40 pm - 9:00 pmDennis Selkoe (Brigham and Women's Hospital, USA)
"Physical and Functional Interaction Between the Alpha- and Gamma-Secreatases: A New Model of Regulated Intramembrane Proteolysis"
9:00 pm - 9:10 pmDiscussion
9:10 pm - 9:25 pmStephen Blacklow (Harvard Medical School, USA)
"Structural Basis for Regulated Proteolysis by the Alpha-Secretase ADAM10"
9:25 pm - 9:30 pmDiscussion
Tuesday
7:30 am - 8:30 amBreakfast
8:30 amGroup Photo
9:00 am - 12:30 pmMMPs and TIMPs as Targets and Anti-Targets in Cancer
Discussion Leader: Sharon Stack (University of Notre Dame, USA)
9:00 am - 9:15 amIntroduction by Discussion Leader
9:15 am - 9:35 amAchim Kruger (Rechts der Isar Hospital, Technical University of Munich, Germany)
"TIMP-1 Signaling as an Accomplice in Liver Metastasis"
9:35 am - 9:45 amDiscussion
9:45 am - 10:05 amBarbara Fingleton (Vanderbilt University, USA)
"A Perplexing Target: Opposing Functions of MMP10 in Colon Cancer"
10:05 am - 10:15 amDiscussion
10:15 am - 10:35 amChristopher Overall (University of British Columbia, Canada)
"Tumor Associated Macrophage MMP12 Cleaves Intracellular Tumor Oncogene Targets Preventing Cancer Inititiation"
10:35 am - 10:45 amDiscussion
10:45 am - 11:15 amCoffee Break
11:15 am - 11:25 amSatsuki Mochizuki (National Defense Medical College, Japan)
"Regulation of Tumor Microenvironmental Factors by ADAM28"
11:25 am - 11:30 amDiscussion
11:30 am - 11:40 amTamar Feinberg (University of Michigan, USA)
"A Proteolytic ECM-Remodeling Axis Governs Breast Tumor Cell Invasion and Metastasis In Vivo"
11:40 am - 11:45 amDiscussion
11:45 am - 11:55 amMarie Kveiborg (University of Copenhagen, Denmark)
"Loss of ADAM9 Expression Impairs β1 Integrin Endocytosis, Focal Adhesion Formation and Cancer Cell Migration"
11:55 am - 12:00 pmDiscussion
12:00 pm - 12:15 pmAndreas Ludwig (RWTH Aachen University, Germany)
"The Metalloproteinase ADAM15 Is Upregulated by Shear Stress and Promotes Survival of Endothelial Cells"
12:15 pm - 12:20 pmDiscussion
12:20 pm - 12:30 pmGeneral Discussion
12:30 pmLunch
1:30 pm - 4:00 pmFree Time
4:00 pm - 6:00 pmPoster Session
6:00 pmDinner
7:30 pm - 9:30 pmMMPs: Critical Effectors in Inflammation
Discussion Leader: Christopher Overall (University of British Columbia, Canada)
7:30 pm - 7:40 pmIntroduction by Discussion Leader
7:40 pm - 8:00 pmWilliam Parks (Cedars-Sinai Medical Center, USA)
"MMP10 Drives the Immunosuppressive Activity of Macrophages"
8:00 pm - 8:10 pmDiscussion
8:10 pm - 8:30 pmAthan Kuliopulos (Tufts Medical Center, USA)
"MMP1 Signaling Through Protease-Activated Receptor-1 in Systemic and Vascular Inflammation"
8:30 pm - 8:40 pmDiscussion
8:40 pm - 9:00 pmZhongjun Zhou (The University of Hong Kong, Hong Kong SAR China)
"MT-MMP Sheds LYVE-1 and Suppresses VEGF-C Production to Inhibit Lymphangiogenesis"
9:00 pm - 9:10 pmDiscussion
9:10 pm - 9:20 pmAntoine Dufour (University of British Columbia, Canada)
"Post-Translational Truncation of IFN-? Dampens Proinflammatory Macrophage Responses and Is Reduced in Autoimmune Disease"
9:20 pm - 9:25 pmDiscussion
9:25 pm - 9:30 pmGeneral Discussion
Wednesday
7:30 am - 8:30 amBreakfast
9:00 am - 12:30 pmNovel Approaches to Translate Discoveries to Targeted Therapies
Discussion Leader: William Parks (Cedars-Sinai Medical Center, USA)
9:00 am - 9:15 amIntroduction by Discussion Leader
9:15 am - 9:35 amJoseph Castellano (Stanford University School of Medicine, USA)
"Systemic TIMP2 Treatment Improves Hippocampal Function in Aged Mice"
9:35 am - 9:45 amDiscussion
9:45 am - 10:05 amGuy Salvesen (Sanford Burnham Prebys Medical Discovery Institute, USA)
"Unique Activity Profiles of Inflammatory Proteases"
10:05 am - 10:15 amDiscussion
10:15 am - 10:35 amGregg Fields (Florida Atlantic University, USA)
"MMP Structural Biology for Guiding Selective Inhibitor Design"
10:35 am - 10:45 amDiscussion
10:45 am - 11:15 amCoffee Break
11:15 am - 11:30 amEvette Radisky (Mayo Clinic, USA)
"Development of Therapeutic TIMPs Integrating Structure-Based and Directed Evolution Approaches"
11:30 am - 11:35 amDiscussion
11:35 am - 11:45 amUlrich Auf Dem Keller (ETH Zurich, Switzerland)
"Deciphering Matrix Metalloproteinase Activation Networks in Tissue Repair by Targeted Degradomics"
11:45 am - 11:50 amDiscussion
11:50 am - 12:00 pmPeter Janes (Monash University, Australia)
"Selective Inhibition of Cancer Cell Signalling by Targeting an Active Form of the ADAM10 Metalloprotease in Tumours"
12:00 pm - 12:05 pmDiscussion
12:05 pm - 12:15 pmXavier Gomis-Ruth (Molecular Biology Institute of Barcelona, CSIC, Spain)
"A Structure-Derived Snap-Trap Mechanism of a Multispecific Serpin from the Dysbiotic Oral Microorganism Porphyromonas gingivalis"
12:15 pm - 12:20 pmDiscussion
12:20 pm - 12:30 pmGeneral Discussion
12:30 pmLunch
1:30 pm - 4:00 pmFree Time
4:00 pm - 6:00 pmPoster Session
6:00 pmDinner
7:00 pm - 7:30 pmBusiness Meeting
Nominations for the Next Vice Chair; Fill in Conference Evaluation Forms; Discuss Future Site and Scheduling Preferences; Election of the Next Vice Chair
7:30 pm - 9:30 pmExploiting Metalloproteinase Activity for Diagnosis and Treatment of Disease
Discussion Leader: Dylan Edwards (University of East Anglia, United Kingdom)
7:30 pm - 7:40 pmIntroduction by Discussion Leader
7:40 pm - 8:00 pmPaul Loadman (University of Bradford, United Kingdom)
"Exploiting Tumor Metalloproteinase Expression for Selective Drug Targeting"
8:00 pm - 8:10 pmDiscussion
8:10 pm - 8:30 pmGhislain Opdenakker (University of Leuven, Belgium)
"Gelatinase B or MMP-9: From Target to Useful Disease Marker"
8:30 pm - 8:40 pmDiscussion
8:40 pm - 9:00 pmJeanine D'Armiento (Columbia University, USA)
"MMPis as a Tool for Functional Lung Imaging"
9:00 pm - 9:10 pmDiscussion
9:10 pm - 9:20 pmSumeda Nandadasa (Cleveland Clinic Lerner Research Institute, USA)
"ADAMTS9 and ADAMTS20 Have a Dual Role in the Primary Cilium and ECM Remodeling During Morphogenesis"
9:20 pm - 9:25 pmDiscussion
9:25 pm - 9:30 pmGeneral Discussion
Thursday
7:30 am - 8:30 amBreakfast
9:00 am - 12:30 pmBeyond the Catalytic Site: Endogenous Regulation of Metalloproteinases
Discussion Leaders: Gillian Murphy (University of Cambridge, United Kingdom) and Hideaki Nagase (University of Oxford, United Kingdom)
9:00 am - 9:15 amIntroduction by Discussion Leader
9:15 am - 9:35 amStefan Linder (Medical Center Hamburg-Eppendorf, Germany)
"MT1-MMP Transport and Structural Memory in Macrophages"
9:35 am - 9:45 amDiscussion
9:45 am - 10:05 amStephen Weiss (University of Michigan, USA)
"Exocyst-Dependent Control of MT-MMP Trafficking: The Trans-Golgi-to-Invadapodia Highway"
10:05 am - 10:15 amDiscussion
10:15 am - 10:30 amYoshifumi Itoh (University of Oxford, United Kingdom)
"Signalling Through the Collagen Receptor, DDR1, Is Required for Epithelial Polarisation and Morphological Remodelling in 3D Collagen Matrices"
10:30 am - 10:35 amDiscussion
10:35 am - 11:05 amCoffee Break
11:05 am - 11:25 amChristoph Becker-Pauly (University of Kiel, Germany)
"Shedding and Activation of Meprin Beta Regulates Intestinal Host Defense"
11:25 am - 11:35 amDiscussion
11:35 am - 11:45 amGeneral Discussion
11:45 am - 11:55 amRahel Schnellmann (Friedrich Miescher Institute for Biomedical Research, Switzerland)
"Characterization of the Metalloproteinase ADAMTS16 and Its Role in Fibronectin Assembly"
11:55 am - 12:00 pmDiscussion
12:00 pm - 12:10 pmWei-Hsuan Yu (National Taiwan University, Taiwan)
"MUC-1 SEA Domain Shedding Protease, Matrilysin, Mediates Nucleolus Trafficking for Gamma-Catenin and p53 and Bulky-Ball-Like Nucleolus Assembly in Cancer Stem Cells"
12:10 pm - 12:15 pmDiscussion
12:15 pm - 12:25 pmSanjay Saw (University Health Network, Canada)
"Mammalian Skeletal Symmetry Relies on the TIMP Gene Family"
12:25 pm - 12:30 pmDiscussion
12:30 pmLunch
1:30 pm - 4:00 pmFree Time
4:00 pm - 6:00 pmPoster Session
6:00 pmDinner
7:30 pm - 9:30 pmTranslational Approaches in Protease-Driven Diseases
Discussion Leader: Rama Khokha (Princess Margaret Cancer Centre, Canada)
7:30 pm - 7:45 pmIntroduction by Discussion Leader
7:45 pm - 8:05 pmAndreas Herrlich (Harvard Medical School, USA)
"
The Role of ADAM17 and Its Substrates in Kidney Fibrosis
"
8:05 pm - 8:15 pmDiscussion
8:15 pm - 8:35 pmJuliane Bubeck Wardenburg (Washington University in St. Louis, USA)
"Protease Inhibition for the Treatment of Sepsis"
8:35 pm - 8:45 pmDiscussion
8:45 pm - 9:05 pmStefan Rose-John (University of Kiel, Germany)
"ADAM17 in the Control of Inflammation and Cancer"
9:05 pm - 9:15 pmDiscussion
9:15 pm - 9:25 pmGeneral Discussion
9:25 pm - 9:30 pmClosing Remarks
Friday
7:30 am - 8:30 amBreakfast
9:00 amDeparture
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