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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
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Ma Qiaoli, Dieterich Lothar C, Detmar Michael (2019), Multiple roles of lymphatic vessels in tumor progression, in Current Opinion in Immunology
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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.