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.

项目概要 乳腺癌是女性癌症死亡的第二大原因，仅次于肺癌。其中 不同亚型，不表达雌激素受体的三阴性乳腺癌（TNBC）， 黄体酮受体和人表皮生长因子受体 2 的特点是预后不良 结果。 TNBC 形成具有高间质液压力 (IFP) 的实体瘤。高IFP促进肿瘤发生 在具有高 IFP 的 TNBC 肿瘤中，癌症的免疫治疗也会受到多种影响 因为间质压力阻止免疫细胞浸润到肿瘤中。而纤维化形成的固体应力 肿瘤细胞外基质有助于肿瘤 IFP 形成、高通透性血管以及 淋巴引流受损，导致高 IFP。为了减少肿瘤 IFP，研究人员尝试减少 固体压力并使肿瘤中的渗漏血管正常化。然而，肿瘤中淋巴引流如何受损 微环境以及受损的淋巴功能如何影响肿瘤 IFP、免疫细胞相互作用和抗- 肿瘤免疫仍不明确。多项研究表明，淋巴管 (LV) 在结构上 肿瘤和淋巴管生成血管内皮生长因子 C (VEGFC) 功能受损 治疗通过促进淋巴管生成和促进 T 细胞向肿瘤的募集来抑制肿瘤生长。 然而，VEGFC也被认为可以促进淋巴结转移。鉴于相互矛盾的影响 VEGFC，该项目的主要目标是在不使用 VEGFC 或 通过破译淋巴管内皮细胞（LEC）连接的机制，不促进淋巴管生成 TNBC 的改造。在本提案中，我们将使用淋巴管的生理响应体外 3D 系统 与乳腺癌细胞共培养的血管，可以重现淋巴结构、淋巴引流和 乳腺癌中的免疫细胞相互作用。通过这些器官型 3D 模型系统，我们将检查淋巴管 在组织样和体内环境的背景下，TNBC 中的连接形态发生和引流，检查 TNBC 相关 LEC 中的 LEC 连接拉链，评估树突状细胞中淋巴功能的作用 运输至淋巴管、T 细胞激活以及肿瘤中的 T 细胞浸润；并评估 LEC 连接的作用 抗肿瘤免疫拉链。如果成功，我们的研究不仅将确定治疗乳腺癌的新靶点， 还为机制研究和快速筛选治疗癌症的潜在候选药物提供了新工具 和淋巴疾病。