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The role of lymphatic vessels in cancer progression

English title The role of lymphatic vessels in cancer progression
Applicant Detmar Michael
Number 166490
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Experimental Cancer Research
Start/End 01.05.2016 - 30.04.2019
Approved amount 824'108.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Pathophysiology

Keywords (3)

lymphangiogenesis; podoplanin; cancer metastasis

Lay Summary (German)

Lead
Krebs breitet sich oft über die Lymphgefässe im Körper aus. Ziel des Projekts ist ein besseres Verständnis der Mechanismen, mit denen Lymphgefässe die Tumorausbreitung fördern, um neue Ziele für die Krebsbehandlung zu identifizieren.
Lay summary
In früheren Studien identifizierte unsere Arbeitsgruppe einen neuen Mechanismus der Krebsausbreitung: Maligne Tumoren können das Wachstum von Lymphgefässen im Tumor und in Lymphknoten mit Hilfe von Botenstoffen anregen, um damit die Absiedlung von Krebszellen zu fördern. Das Ziel des Projekts ist nun die detaillierte Charakterisierung der Mechanismen, mit Hilfe derer Lymphgefässe in Lymphknoten und in Organmetastasen das Wachstum und die weitere Absiedlung von Tumorzellen fördern. Hierfür werden Gensequenzierungen von Lymphgefässzellen durchgeführt, um Gene zu identifizieren, die in tumordrainierenden Lymphgefässen aktiv sind. Weiterhin werden Organmetastasen auf das Wachstum von Lymphgefässen und den Zusammenhang von Lymphgefässwachstum und weiterer Tumorabsiedlungen untersucht. Ein weiterer Schwerpunkt des Projekts liegt auf der Charakterisierung der Rolle des Proteins Podoplanin für das Wachstum und die Tumorabsiedlung von Hautkrebs. Insbesondere wird vergleichend untersucht, welchen Einfluss die Produktion von Podoplanin in Epithelzellen oder in Lymphgefässzellen auf die Tumorausbreitung hat. Diese Untersuchungen stellen die Grundlagen für die Entwicklung neuer therapeutischer Strategien für die Krebsbehandlung dar.
Direct link to Lay Summary Last update: 30.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
A Distinct Role of the Autonomic Nervous System in Modulating the Function of Lymphatic Vessels under Physiological and Tumor-Draining Conditions
Bachmann Samia B., Gsponer Denise, Montoya-Zegarra Javier A., Schneider Martin, Scholkmann Felix, Tacconi Carlotta, Noerrelykke Simon F., Proulx Steven T., Detmar Michael (2019), A Distinct Role of the Autonomic Nervous System in Modulating the Function of Lymphatic Vessels under Physiological and Tumor-Draining Conditions, in Cell Reports, 27(11), 3305-3314.e13.
Differential effects of anaesthesia on the contractility of lymphatic vessels in vivo
Bachmann Samia B., Proulx Steven T., He Yuliang, Ries Miriam, Detmar Michael (2019), Differential effects of anaesthesia on the contractility of lymphatic vessels in vivo, in The Journal of Physiology, JP277254-JP277254.
Inflammation and Lymphatic Function
Schwager Simon, Detmar Michael (2019), Inflammation and Lymphatic Function, in Frontiers in Immunology, 10(308), 1-11.
Antibody-mediated delivery of VEGF-C potently reduces chronic skin inflammation
Schwager Simon, Renner Silvana, Hemmerle Teresa, Karaman Sinem, Proulx Steven T., Fetz Roman, Golding-Ochsenbein Alexandra Michaela, Probst Philipp, Halin Cornelia, Neri Dario, Detmar Michael (2018), Antibody-mediated delivery of VEGF-C potently reduces chronic skin inflammation, in JCI Insight, 3(23), 124850.
Alternative transcription of a shorter, non-anti-angiogenic thrombospondin-2 variant in cancer-associated blood vessels
Roudnicky Filip, Yoon Sun Young, Poghosyan Susanna, Schwager Simon, Poyet Cedric, Vella Giorgia, Bachmann Samia B., Karaman Sinem, Shin Jay W., Otto Vivianne I., Detmar Michael (2018), Alternative transcription of a shorter, non-anti-angiogenic thrombospondin-2 variant in cancer-associated blood vessels, in Oncogene, 37(19), 2573-2585.
Tumor-Associated Lymphatic Vessels Upregulate PDL1 to Inhibit T-Cell Activation
Dieterich Lothar C., Ikenberg Kristian, Cetintas Timur, Kapaklikaya Kübra, Hutmacher Cornelia, Detmar Michael (2017), Tumor-Associated Lymphatic Vessels Upregulate PDL1 to Inhibit T-Cell Activation, in Frontiers in Immunology, 8, 66.

Collaboration

Group / person Country
Types of collaboration
Prof. Burkhard Becher, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Kari Alitalo, Univ. of Helsinki Finland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Mitch Levesque, Dept. of Dermatology, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Steve Watson Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Taija Mäkinen, Uppsala University Sweden (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Guillermo Oliver, Northwestern University, Chicago United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Awards

Title Year
ETH Medal für die beste Doktorarbeit 2019

Associated projects

Number Title Start Funding scheme
185392 Role of lymphatic vessels in cancer progression 01.05.2019 Project funding (Div. I-III)
185392 Role of lymphatic vessels in cancer progression 01.05.2019 Project funding (Div. I-III)
147087 Molecular mechanisms of angiogenesis and lymphangiogenesis in inflammation and cancer progression 01.05.2013 Project funding (Div. I-III)

Abstract

Our previous studies have identified a critical role of tumor lymphangiogenesis and lymph node lymphangiogenesis in the promotion of cancer metastasis. More recently, we identified that lymphatic vessels may also promote the growth of and further malignant tumor spread from distant organ metastases. Furthermore, our studies in experimental tumor models and in human head-and-neck cancers indicate an important role of the glycoprotein podoplanin in promoting tumor lymphangiogenesis, invasion and metastasis. We now propose experiments to test our specific hypotheses: (1) that tumor-activated lymphatic vessels in tumor-draining lymph nodes and in organ metastases upregulate genes that promote cancer metastasis and that might serve as novel biomarkers for cancer progression, (2) that lymphatic vessels play a major role in the growth of organ metastases and in the further metastatic spread from organ metastases, and (3) that both lymphatic-expressed podoplanin and tumor cell-expressed podoplanin play important roles in promoting tumor lymphangiogenesis and cancer metastasis. Understanding the mechanisms of lymphatic vessel activation will be the basis for developing novel therapeutic strategies to treat advanced cancer.Aim 1: Identify molecular mechanisms with importance for tumor-induced lymph node lymphangiogenesis.1.1. Identify the global transcriptional changes induced in lymphatic vessels of metastatic lymph nodes draining experimental melanomas and breast cancers, as compared with lymphatic vessels of normal lymph nodes. 1.2. Determine the in situ expression and the in vitro and in vivo functions of identified candidate genes, using in situ hybridization, loss-of-function and gain-of-function approaches in cultured lymphatic endothelial cells and in melanoma and breast cancer models. Aim 2: Define the importance of lymphatic vessel activation for distant organ metastasis.2.1. Investigate the regulation of lymphangiogenesis in distant organ metastases of human melanomas and in experimental tumor models.2.2. Determine the influence of lymphatic vessels on metastatic tumor growth and further metastasis, using tumor cell lines and an inducible lung-specific VEGF-C overexpression mouse model.2.3. Identify biomarkers and therapeutic targets related to organ metastases-associated lymphatic vessels. Aim 3: Define the role of lymphatic vessel-expressed versus epidermal keratinocyte-expressed podoplanin in cutaneous tumor growth, lymphangiogenesis and lymphatic versus organ metastasis in inducible and targeted knockout mice. 3.1. Determine the impact of the lymphatic marker gene podoplanin on tumor progression, lymphangiogenesis and lymphatic versus organ metastasis of squamous cell carcinomas, that are chemically induced in the skin of mice with inducible lymphatic vessel-targeted deletion of podoplanin or with epidermis-targeted deletion of podoplanin.
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