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.
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
Schwager Simon, Detmar Michael (2019), Inflammation and Lymphatic Function, in Frontiers in Immunology
, 10(308), 1-11.
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.
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.
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.
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.