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Role of lymphatic vessels in cancer progression

English title Role of lymphatic vessels in cancer progression
Applicant Detmar Michael
Number 185392
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 01.05.2019 - 31.01.2022
Approved amount 634'278.00
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Keywords (3)

lymphangiogenesis; lymphatic endothelium; metastasis

Lay Summary (German)

Lead
Die Rolle der Lymphgefässe in der Krebsausbreitung.
Lay summary
Lymphknotenmetastasen stellen häufig die erste Etappe der Ausbreitung bösartiger Tumore dar und sind bei vielen Krebsarten, einschliesslich malignem Melanom und Brustkrebs, wichtige prognostische Faktoren. Vor mehr als 15 Jahren entdeckten wir und andere Forschungsgruppen einen neuen Mechanismus der Krebsausbreitung: Tumoren können das Wachstum von Lymphgefässen induzieren ("Lymphangiogenese"), um somit ihre Ausbreitung in die sogenannten Wächter-Lymphknoten zu beschleunigen. Ebenfalls können Tumoren bereits vor ihrer Absiedlung das Wachstum von Lymphgefässen in den Lymphknoten fördern. Kürzlich konnten wir erstmalig nachweisen, dass das Wachstum von neuen Lymphgefässen auch in Lungenmetastasen nachzuweisen ist, und dass diese Lymphgefässe die weitere Tumorausbreitung in andere Organe fördern. 
Obwohl diese Befunde eine wichtige Rolle der Lymphgefässe in der Krebsausbreitung identifizierten, sind die genauen zellulären und molekularen Mechanismen nicht vollständig aufgeklärt. Unsere geplanten Studien sollen neue Einsichten in diese Mechanismen ermöglichen und mögliche neue Zielstrukturen für die Behandlung von fortgeschrittenen Krebserkrankungen identifizieren.
Hierfür werden wir zunächst abklären, welche Rolle ein bestimmtes Membranprotein (ein "Integrin") auf den Lymphgefässen der Lymphknoten für die Tumorausbreitung spielt. Weiterhin werden wir eine neue Technologie anwenden, um die Genexpression in Hunderten von einzelnen lymphatischen Endothelzellen zu vergleichen, die aus gesunden Lymphknoten und aus tumordrainierenden Wächter-Lymphknoten isoliert werden. Schliesslich werden wir die Funktion eines bestimmten Transkriptionsfaktor für die Funktion der Lymphgefässe in verschiedenen Organen und für die Tumorausbreitung untersuchen.
Direct link to Lay Summary Last update: 07.04.2019

Responsible applicant and co-applicants

Employees

Publications

Publication
LETR1 is a lymphatic endothelial-specific lncRNA governing cell proliferation and migration through KLF4 and SEMA3C
Ducoli Luca, Agrawal Saumya, Sibler Eliane, Kouno Tsukasa, Tacconi Carlotta, Hon Chung-Chao, Berger Simone D., Müllhaupt Daniela, He Yuliang, Kim Jihye, D’Addio Marco, Dieterich Lothar C., Carninci Piero, de Hoon Michiel J. L., Shin Jay W., Detmar Michael (2021), LETR1 is a lymphatic endothelial-specific lncRNA governing cell proliferation and migration through KLF4 and SEMA3C, in Nature Communications, 12(1), 925-925.
CD169+ lymph node macrophages have protective functions in mouse breast cancer metastasis
Tacconi Carlotta, Commerford Catharina D., Dieterich Lothar C., Schwager Simon, He Yuliang, Ikenberg Kristian, Friebel Ekaterina, Becher Burkhard, Tugues Sònia, Detmar Michael (2021), CD169+ lymph node macrophages have protective functions in mouse breast cancer metastasis, in Cell Reports, 35(2), 108993-108993.
Keratinocyte-Expressed Podoplanin is Dispensable for Multi-Step Skin Carcinogenesis
Sesartić Marko, Ikenberg Kristian, Yoon Sun-Young, Detmar Michael (2020), Keratinocyte-Expressed Podoplanin is Dispensable for Multi-Step Skin Carcinogenesis, in Cells, 9(6), 1542-1542.
Single-cell mapping reveals new markers and functions of lymphatic endothelial cells in lymph nodes
Fujimoto Noriki, He Yuliang, D’Addio Marco, Tacconi Carlotta, Detmar Michael, Dieterich Lothar C. (2020), Single-cell mapping reveals new markers and functions of lymphatic endothelial cells in lymph nodes, in PLOS Biology, 18(4), e3000704-e3000704.
Mechanisms of Tumor-Induced Lymphovascular Niche Formation in Draining Lymph Nodes
Commerford Catharina D., Dieterich Lothar C., He Yuliang, Hell Tanja, Montoya-Zegarra Javier A., Noerrelykke Simon F., Russo Erica, Röcken Martin, Detmar Michael (2019), Mechanisms of Tumor-Induced Lymphovascular Niche Formation in Draining Lymph Nodes, in Cell Reports, 25(13), 3554-3563.e4.
Unexpected contribution of lymphatic vessels to promotion of distant metastatic tumor spread
Ma Qiaoli, Dieterich Lothar C., Ikenberg Kristian, Bachmann Samia B., Mangana Johanna, Proulx Steven T., Amann Valerie C., Levesque Mitchell P., Dummer Reinhard, Baluk Peter, McDonald Donald M., Detmar Michael (2019), Unexpected contribution of lymphatic vessels to promotion of distant metastatic tumor spread, in Science Advances, 4(8), 4758.
Multiple roles of lymphatic vessels in tumor progression
Ma Qiaoli, Dieterich Lothar C, Detmar Michael (2019), Multiple roles of lymphatic vessels in tumor progression, in Current Opinion in Immunology, 53, 7-12.
Transcriptional profiling of breast cancer‐associated lymphatic vessels reveals VCAM‐1 as regulator of lymphatic invasion and permeability
Dieterich Lothar C., Kapaklikaya Kübra, Cetintas Timur, Proulx Steven T., Commerford Catharina D., Ikenberg Kristian, Bachmann Samia B., Scholl Jeannette, Detmar Michael (2019), Transcriptional profiling of breast cancer‐associated lymphatic vessels reveals VCAM‐1 as regulator of lymphatic invasion and permeability, in International Journal of Cancer, 145(10), 2804-2815.

Associated projects

Number Title Start Funding scheme
166490 The role of lymphatic vessels in cancer progression 01.05.2016 Project funding (Div. I-III)
166490 The role of lymphatic vessels in cancer progression 01.05.2016 Project funding (Div. I-III)

Abstract

Lymph node metastasis is frequently the first step of tumor dissemination and is currently the most important prognostic factor in several human cancer types, including malignant melanoma and breast cancer. More than 15 years ago, we and others discovered that tumors can induce the growth of lymphatic vessels (lymphangiogenesis) and that tumor lymphangiogenesis promotes further metastasis to the draining (sentinel) lymph nodes. Moreover, solid tumors can also induce lymphangiogenesis in their draining lymph nodes, often even before any metastatic tumor cells are detectable, thus preparing a pre-metastatic niche. Both of these concepts, originally obtained in experimental mouse models, have been confirmed in a multitude of clinical studies in several types of cancer. Very recently, we made the surprising discovery that lymphangiogenesis is also induced in lung metastases of experimental breast cancers and melanomas, and of human malignant melanomas, and that lymphatic vessels also play a role in the further spread of distant organ metastases to other organs. Together, these studies reveal an important role of lymphatic vessels in tumor progression and metastasis. However, the cellular and molecular mechanisms how lymphatic endothelium promotes cancer progression have remained less clear, and blockade of the individual contributions of lymphatic vessels to tumor metastasis might represent a novel therapeutic approach. We now propose studies to pursue the following three aims:Aim 1: Investigate specific molecular mechanisms with importance for tumor-induced lymph node lymphangiogenesis.1.1. Investigate the regulation of integrin aIIb on lymphatic vessels in tumor-draining lymph nodes. 1.2. Determine the biological role of integrin aIIb in tumor growth and lymph node lymphangiogenesis in vivo. Aim 2: Identify lymphatic endothelial cell subtype-specific molecular mechanisms with importance for tumor-induced lymph node lymphangiogenesis.2.1. Investigate by single cell sequencing the subtypes of lymphatic endothelial cells in normal and in tumor-draining lymph nodes. 2.2. Investigate by single cell sequencing the lymphatic endothelial cell subtype-specific transcriptional changes in tumor-draining lymph nodes.Aim 3: Define the importance of lymphatic expression of the transcription factor MAFB for the physiological and pathological formation and function of lymphatic vessels.3.1. Investigate the morphology and function of lymphatic vessels in different organs of mice with lymphatic vessel-specific mafb deletion.3.2. Investigate tumor and lymph node lymphangiogenesis and metastasis in mice with lymphatic vessel-specific mafb deletion.
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