Tissue-Engineered Models of Lymphatic Drainage in Breast Cancer

项目摘要 乳腺癌是妇女癌症死亡的第二大原因，仅次于肺癌。中 不同亚型，不表达雌激素受体的三阴性乳腺癌（TNBC）， 孕激素受体和人表皮生长因子受体2，其特征是预后不良， 结果。TNBC形成具有高间质流体压力（IFP）的实体瘤。高IFP促进肿瘤 在具有高IFP的TNBC肿瘤中，几种方式和癌症免疫治疗也受到损害 因为间质压力阻止免疫细胞渗入肿瘤。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，高渗透性血管，结合 淋巴引流受损导致IFP升高为了减少肿瘤IFP，研究人员试图减少 固体应力和正常化肿瘤中的渗漏血管。然而，淋巴引流如何在肿瘤中受损， 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功能。 肿瘤免疫仍不明确。几项研究报道，淋巴管（LV）在结构上是 和淋巴管生成血管内皮生长因子C（VEGFC） 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也被认为促进淋巴结转移。考虑到 VEGFC，该项目的主要目标是使TNBC中的淋巴引流正常化，而不使用VEGFC或 不促进淋巴管生成，通过破译淋巴管内皮细胞（LEC）连接的机制， 在TNBC重塑。在这项提议中，我们将使用生理反应的体外3D淋巴系统， 与乳腺癌细胞共培养的血管，可以重现淋巴结构，淋巴引流， 乳腺癌的免疫细胞相互作用。有了这些器官型3D模型系统，我们将检查淋巴 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LEC连接拉链，评估淋巴功能在树突状细胞中的作用 肿瘤中T细胞向淋巴细胞的转运、T细胞活化和T细胞浸润;并评估LEC连接的作用 增强抗肿瘤免疫力如果成功的话，我们的研究不仅会发现治疗乳腺癌的新靶点， 也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的工具 和淋巴疾病。

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.