Tissue-Engineered Models of Lymphatic Drainage in Breast Cancer

乳腺癌淋巴引流的组织工程模型

• 批准号: 10637169
• 负责人: Esak Lee
• 金额: $ 41.04万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-23 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637169
• 关键词: 3-Dimensional; Affect; Binding; Biological Models; Biology; Biomedical Engineering; Blood; Blood Vessels; Boston; Brain; Breast; Breast Cancer Cell; CAR T cell therapy; Cancer Etiology; Cell Communication; Cells; Cessation of life; Coculture Techniques; Collaborations; Complex; Dendritic Cells; Drainage procedure; Endothelial Cells; Environment; Epidermal Growth Factor Receptor; Estrogen Receptors; Extracellular Matrix; Goals; Human; Immune; Immune Evasion; Immune System Diseases; Immunologist; Immunotherapy; Impairment; In Vitro; Infiltration; Intercellular Fluid; Intercellular Junctions; Knockout Mice; Lead; Lymphangiogenesis; Lymphatic; Lymphatic Diseases; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic function; Malignant Neoplasms; Malignant neoplasm of lung; Mammary Neoplasms; Matrix Metalloproteinases; Mediating; Medicine; Meningeal lymphatic system; Metastatic Neoplasm to Lymph Nodes; Modeling; Morphogenesis; Mucin 1 protein; Neoplasms in Vascular Tissue; Oncologist; Organ; Outcome; Pediatric Hospitals; Physiological; Progesterone Receptors; Protein Kinase; ROCK1 gene; Regulation; Reporting; Research Personnel; Role; Small Intestines; Solid; Solid Neoplasm; Stress; Structure; T cell infiltration; T-Cell Activation; T-Lymphocyte; Tissue Engineering; Tissues; Tumor Immunity; Tumor Promotion; Vascular Endothelial Growth Factor C; Vascular System; Woman; angiogenesis; cancer cell; cancer immunotherapy; cell motility; cytokine; drug candidate; functional disability; immune cell infiltrate; in vivo; inhibitor; interstitial; lacteal; lymphatic Invasion; lymphatic drainage; lymphatic dysfunction; lymphatic vessel; malignant breast neoplasm; mammary epithelium; pressure; prognostic; recruit; rho; screening; synergism; targeted treatment; three-dimensional modeling; tool; trafficking; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions

PROJECT SUMMARY Breast cancer is a second leading cause of cancer death in women, exceeded only by lung cancer. Among the different subtypes, triple-negative breast cancer (TNBC) that does not express the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, is characterized by poor prognostic outcomes. TNBC forms solid tumors with high interstitial fluid pressure (IFP). High IFP promotes tumor progression several ways and cancer immunotherapies are also compromised in TNBC tumors with high IFP since the interstitial pressure keeps immune cells from infiltrating into tumors. While solid stress formed by fibrotic tumor extracellular matrix contributes to tumor IFP formation, hyperpermeable blood vessels, combined with compromised lymphatic drainage, lead to high IFP. To decrease tumor IFP, researchers have tried to reduce solid stress and normalize leaky blood vessels in tumors. However, how lymphatic drainage is impaired in tumor microenvironment and how the impaired lymphatic function affects tumor IFP, immune cell interactions, and anti- tumor immunity are still ambiguous. Several studies have reported that lymphatic vessels (LVs) are structurally and functionally impaired in tumors, and lymphangiogenic vascular endothelial growth factor C (VEGFC) treatment inhibited tumor growth by promoting lymphangiogenesis and boosting T cell recruitment to the tumors. However, VEGFC has also been recognized to promote lymph node metastasis. Given the conflicting effects of VEGFC, the main goals of this project are to normalize lymphatic drainage in TNBC without using VEGFC or without promoting lymphangiogensis, by deciphering the mechanisms of lymphatic endothelial cell (LEC) junction remodeling in TNBC. In this proposal, we will use physiologically responsive in vitro 3D systems of lymphatic vessels co-cultured with breast cancer cells, which can recapitulate lymphatic structure, lymphatic drainage, and immune cell interactions in breast cancer. With these organotypic 3D model systems, we will examine lymphatic junction morphogenesis and drainage in TNBC in the context of a tissue-like and in vivo environment, examine LEC junction zippering in TNBC-associated LECs, evaluate the roles of lymphatic function in dendritic cell trafficking to lymphatics, T cell activation, and T cell infiltration in tumors; and assess the roles of LEC junction zippering for anti-tumor immunity. If successful, our studies will not only identify new targets to treat breast cancer, but also provide a new tool for mechanism studies and fast screening of potential drug candidates to treat cancer and lymphatic disease.

项目总结