Exosomal CD44 in the metastasis of triple negative breast cancer

摘要 这项建议的目的是确定乳腺癌细胞分泌的外切体的功能。 在调节肿瘤的运动性、干性和免疫逃避方面。我们的初步结果表明 循环中的肿瘤细胞聚集成簇并促进多克隆的干性 三阴性乳腺癌的转移(TNBC)(癌症发现，2019年)。我们还发现， 肿瘤外切体诱导肿瘤受体细胞的聚集和迁移。教育人 带有癌症外切体的白细胞抑制免疫细胞，并抑制其杀瘤作用。一个 越来越多的证据突显了外体在细胞通讯中的作用，以及 胞外体蛋白对转移生态位和肿瘤免疫的调节作用 微环境；然而，癌症外切体在癌症干细胞和免疫中的作用 监管没有得到澄清。我们假设癌症外切体促进肿瘤的转移 并抑制中性粒细胞介导的抗肿瘤免疫。按顺序 为了验证我们的假设，我们将：1)检验肿瘤外切体在肿瘤干性中的作用 受体细胞和2)确定癌症外切体在中性粒细胞抑制中的作用。我们 有优化的程序来分离外体，表征它们，并执行功能 学习。人患者来源异种移植(PDX)模型、MDA-MB-231细胞和小鼠 乳腺肿瘤模型E0771和4T1将用于检测癌症外切体的功能。 人类和小鼠的免疫细胞将从血液中分离出来，用于外周教育和 肿瘤-免疫细胞相互作用分析。总而言之，这项研究的目的是确定癌症 外切体是治疗肿瘤干细胞和免疫抑制的新靶点。

Abstract The objective of this proposal is to determine the functions of breast cancer cell-secreted exosomes in regulating tumor motility, stemness, and immune evasion. Our preliminary results demonstrate that circulating tumor cells (CTCs) aggregate to form clusters and promote stemness for polyclonal metastases in triple negative breast cancer (TNBC) (Cancer Discovery, 2019). We also found that cancer exosomes induce the clustering and migration of tumor recipient cells. Educating human leucocytes with cancer exosomes inhibit immune cells, and suppress its tumor-killing effects. A growing body of evidence highlights the role of exosomes in cellular communications, and regulatory effects of exosomal proteins on metastatic niche and tumor immune microenvironment; however, the role of cancer exosomes in cancer stemness and immune regulation is not elucidated. We hypothesize that cancer exosomes promote metastasis of breast tumor cells and suppress neutrophil-mediated anti-tumor immunity in TNBC. In order to test our hypothesis we will: 1) examine the role of tumor exosomes in the stemness of tumor recipient cells and 2) determine the role of cancer exosomes in neutrophil suppression. We have optimized protocols to isolate exosomes, characterize them, and perform functional studies. Human patient-derived xenograft (PDX) models, MDA-MB-231 cells, and mouse breast tumor models E0771 and 4T1 will be used to examine the functions of cancer exosomes. Human and mouse immune cells will be isolated from the blood for exosome education and tumor-immune cell interaction analyses. Taken together, this study aims to determine if cancer exosomes serve as a new therapeutic target for both stemness and immunosuppression in TNBC.