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Identification of Dipeptidase-1 As an Organ-Selective Adhesion Receptor Utilized by Neutrophils and Metastatic Cancer Cells in the Liver and Lungs

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Identification of Dipeptidase-1 As an Organ-Selective Adhesion Receptor Utilized by Neutrophils and Metastatic Cancer Cells in the Liver and Lungs University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2018-04-30 Identification of dipeptidase-1 as an organ-selective adhesion receptor utilized by neutrophils and metastatic cancer cells in the liver and lungs Roy Choudhury, Saurav Roy Choudhury, S. (2018). Identification of dipeptidase-1 as an organ-selective adhesion receptor utilized by neutrophils and metastatic cancer cells in the liver and lungs (Unpublished doctoral thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/31901 http://hdl.handle.net/1880/106619 doctoral thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY Identification of dipeptidase-1 as an organ-selective adhesion receptor utilized by neutrophils and metastatic cancer cells in the liver and lungs by Saurav Roy Choudhury A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN MEDICAL SCIENCE CALGARY, ALBERTA APRIL, 2018 © Saurav Roy Choudhury 2018 Abstract Lungs and liver are two major sites of neutrophil trafficking and inflammatory disease. Neutrophil recruitment in response to an inflammatory cue is a sequentially coordinated process where adhesion molecules expressed on the endothelium of a given organ mediate different steps in the classical leukocyte recruitment cascade [1]. However, molecules identified as being central in the canonical schema of neutrophil recruitment to different organs (mesentery, skin, and cremaster muscle) are not required in the inflamed pulmonary and hepatic vasculatures [2-8]. Using an unbiased functional screen in vivo, we isolated a peptide-displaying phage that homed to the liver and lungs of mice treated with a bacterial inflammatory stimulus (lipopolysaccharide). Employing intravital microscopy, we found that this phage, or its corresponding displayed-peptide, termed LSALT herein, inhibited the adhesion of neutrophils in the inflamed lungs and liver vasculatures in response to LPS. The corresponding synthetic peptide also reduced the metastatic colonization of melanoma cells to the lungs in human xenograft and immunocompetent mouse models. Using biochemical, genetic and confocal intravital imaging approaches we identified dipeptidase-1 (DPEP1) as the functional target of this peptide and established its role as a physical adhesion receptor for neutrophil and metastatic cancer cell adhesion independent of its enzymatic activity. Importantly, genetic ablation or functional peptide blocking of DPEP1 significantly reduced neutrophil recruitment and cancer metastasis to the lungs and liver, and in models of Acute Respiratory Distress Syndrome (ARDS), prevented septic lung injury and mortality. This study identified DPEP1 as an organ-selective vascular endothelial adhesion receptor for the recruitment of neutrophils and metastatic cancer cells to the lungs and liver and identifies DPEP1 as a novel therapeutic target for systemic inflammatory disorders as well as organ-selective metastatic diseases. 1 Graphical abstract 2 Thesis Objective At the time when this thesis project was initiated, the underlying mechanism of cell recruitment to the lungs and liver were unknown. This study was initiated and driven based on an observation that lungs and liver use additional (non-canonical) adhesion molecules for organ selective endothelial binding and recruitment. Despite the established role of classical adhesion receptors (selectins and integrins) in the neutrophil recruitment cascade in the mesentery, skin and cremaster muscle, studies as well as observations by Dr. Paul Kubes and colleagues at the University of Calgary demonstrated that the recruitment of neutrophils were not impaired in the lungs and liver of mice that were deficient in either of these families of classical adhesion receptors. These observations led to the notion that, there are additional molecules involved in the lungs and liver vascular beds that mediate the recruitment of neutrophils to these organs. In 2008, McDonald et al. provided evidence that the interaction of neutrophil-CD44 and endothelial- hyaluronan is a dominant mechanism for the sequestration of neutrophils to the inflamed hepatic sinusoids [3]. These observations provided the initial foundation of this study focusing on the central objective to identify novel adhesion molecules expressed on the surface of inflamed pulmonary and hepatic vascular beds that play a requisite role in the recruitment of neutrophils to these organs in response to inflammation. Employing biochemical, genetic and confocal intravital imaging approaches this study has identified DPEP1 as a major adhesion receptor for the organ- selective recruitment of neutrophils and metastatic cancer cells to the lungs and liver. 3 Preface A major part of the work presented in this thesis was recently submitted to Cell and is currently under revision. 1. In vivo screen identifies Dipeptidase-1 as a major adhesion receptor for organ-selective neutrophil recruitment in inflamed pulmonary and hepatic vasculatures. Saurav Roy Choudhury, Liane Babes, Jennifer J. Rahn, Bo Young Ahn, Kimberly-Ann R. Goring, Xiaoguang Hao, Andrew K. Chojnacki, Ajitha Thanabalasuriar, Arthur Lau, Erin F. McAvoy, Sébastien Tabariès, Kamala D. Patel, Peter M. Siegel, Daniel A. Muruve, Bryan G. Yipp, Paul Kubes , Stephen M. Robbins and Donna L. Senger (under revision in Cell) In addition to this study, a second manuscript is also presently in preparation. This study demonstrates a novel role of a lung and liver homing peptide (termed LSALT herein) in organ- selective metastatic disease in pre-clinical mouse models. In addition, the findings of this study also identified Dipeptidase-1 as novel mediator of organ-selective metastasis in the lungs and liver. The significant part of this manuscript is presented in different sections of this thesis. 2. Dipeptidase-1, a central mediator of organ-selective metastasis to the lungs and liver. Saurav Roy Choudhury, Jennifer J. Rahn, Xiaoguang Hao, Xueqing Lun, Liane Babes, Bo-Young Ahn, Kimberly-Ann R. Goring, Ngoc Ha Dang, Jennifer King, Sébastien Tabariès, Peter M. Siegel, Stephen M. Robbins and Donna L. Senger (in preparation) 4 3. Immune Surveillance by Renal Phagocytes and Tubular Dipeptidase-1 are Essential for Contrast-Induced Acute Kidney Injury. Arthur Lau, Hyun Jae Chung, Takanori Komada, Jaye M. Platnich, Christina F. Sandall, Saurav R. Choudhury, Justin Chun, Victor Naumenko, Bas G.J. Surewaard, Michelle C. Nelson, Annegret Ulke-Lemée, Paul L. Beck, Hallgrimur Benediktsson, Anthony M. Jevnikar, Sarah L. Snelgrove, Michael J. Hickey, Donna L. Senger, Matthew T. James, Justin A. Macdonald, Paul Kubes, Craig N. Jenne, Daniel A. Muruve (resubmitted to Journal of Clinical Investigation) 5 Acknowledgements The scientific observations presented in this thesis represent a phenomenon that goes beyond the biological parameters. The results unveiled here in this thesis was only feasible from the enormous support and immense dedication from a long list of individuals over the last few years. First and foremost, I would like to express my sincere gratitude to my supervisor Dr. Donna Senger, for her guidance, patience, support, advice and constant encouragement throughout the course of this thesis. Despite the regular complexities in a scientific pursuit, Donna has always inspired me with a positive attitude to consider the ‘big picture’ situations. The extended list of things that I had learned from Donna over the years is difficult to elucidate. To mention a few: ‘science is all about troubleshooting’, ‘three most important things to remember in science: What (research question), Why (rationale), and How (experiments), ‘PhD is not about doing experiments and getting data, it’s about thinking differently’. The following quote of Socrates may summarize my learnings from Donna: “understanding a question is half an answer”-Socrates, Essential Thinker. I want to express my deepest appreciation to Dr. Stephen Robbins for his invaluable guidance and motivational suggestions during the course of my PhD tenure. His innovative ideas and thoughtful interpretations about diverse scientific questions has helped me to learn and acquire divergent thinking. I would also like thank my supervisory committee members, Drs. Kubes, Morris and Schriemer for providing me the valuable guidance and helpful suggestions throughout my PhD tenure. This thesis would never have been possible without the indispensable collaborative contributions from several laboratories within the Cumming School of Medicine at the University of Calgary. The invaluable collaboration with Dr. Paul Kubes provided me the platform to perform my intravital microscopy imaging studies throughout my PhD. In addition, collaborations with Dr. 6 Bryan Yipp’s and Dr. Daniel Muruve’s, laboratories had also provided important insights with regards to my thesis project during the course of my PhD tenure. I thank Dr. Kamala Patel and Dr. Peter Siegel for their collaborations. I would also like to thank the Live Cell Imaging facility within the Snyder Institute for Chronic diseases
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