Primary cancers can induce lymphatic vessel growth (lymphangiogenesis), enhancing metastasis to draining lymph nodes (LNs). We found that tumors also induce lymphangiogenesis in draining LNs, leading to increased cancer spread to distal LNs and beyond. Very recently, we found that lymphatic vessel activation in peripheral tissues and draining LNs also plays a previously unanticipated role in the control of chronic inflammatory diseases. This proposal aims at a comprehensive characterization of the function of lymphatic vessels in inflammation, using a variety of genetic mouse models for enhanced or reduced lymphatic function, novel quantitative techniques for the in vivo imaging of lymphatic function, and a miniaturized 3-dimensional in vitro platform for the high-throughput phenotypic screening of libraries of small, drug-like molecules for modulators of lymphatic function. A genome-wide analysis of the gene expression profile shall be made from lymphatic vessels isolated by high-speed cell sorting and by immuno-laser capture microdissection from tumors and their lymph node metastases, inflamed tissue and its draining lymph nodes, and normal tissues, followed by functional characterization of potential therapeutic targets and diagnostic markers. Finally, we will establish novel genetically fluorescent mouse models for the in vivo real-time imaging of lymphatic activation, and we will develop an innovative approach for the in vivo detection of early micrometastases, using antibody-based PET and near-infrared imaging of tumor-induced stromal changes. These studies will improve our understanding of lymphatic involvement in inflammation and cancer metastasis, and will provide the basis for completely novel approaches to treat and detect inflammation and cancer metastasis.
Field of science
- /medical and health sciences/health sciences/inflammatory diseases
- /medical and health sciences/clinical medicine/oncology/cancer
Call for proposal
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