Lymph node regulation of metastatic fitness and reemergence

转移适应性和复发的淋巴结调节

• 批准号: 10356480
• 负责人: Andrea Rachel Lim
• 金额: $ 8.05万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356480
• 关键词: Acute; Affect; Affinity Chromatography; Aftercare; Animals; Antibodies; Bar Codes; Blood; Blood Circulation; Bone Marrow; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast cancer metastasis; Cancer Cell Growth; Cancer Etiology; Cell Cycle; Cessation of life; Clinical; Clonality; Coculture Techniques; Color; Competence; Complex; Cues; Dangerousness; Deposition; Disease; Endothelium; Excision; Exposure to; Extracellular Matrix; Fibrinogen; Generations; Goals; Grant; Human; Immune; Immune Tolerance; Immunity; In Situ; Inflammation; Inguinal lymph node group; Injections; Intervention; Light; Lipopolysaccharides; Literature; Lung; Lymph; Lymphatic; Lymphatic Endothelial Cells; Malignant Neoplasms; Mediating; Messenger RNA; Metastatic breast cancer; Metastatic to; Modeling; Molecular; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Organ; Outcome; Ovalbumin; Pathway interactions; Patients; Peripheral; Phase; Population; Primary Neoplasm; Proteomics; Regulation; Relapse; Ribosomes; Route; Seeds; Shapes; Site; System; T cell receptor repertoire sequencing; T-Lymphocyte; T-cell receptor repertoire; TNFRSF5 gene; Tail; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Translating; Tumor Antigens; Tumor-infiltrating immune cells; Veins; Work; antigen-specific T cells; cell growth; differential expression; experience; fitness; functional outcomes; immunoregulation; in vivo; in vivo Model; in vivo evaluation; insight; intravital imaging; knock-down; lymph nodes; malignant breast neoplasm; mouse model; neoplastic cell; novel; novel therapeutic intervention; overexpression; peripheral tolerance; prevent; receptor expression; small hairpin RNA; targeted treatment; tumor

PROJECT SUMMARY Metastasis is the most dangerous stage of cancer, responsible for the vast majority of breast cancer-related deaths. Currently, we have no treatments that target metastasis; therefore, it is critical to understand metastatic progression at the molecular, cellular, and tissue levels to develop therapeutic strategies against this disease. This proposal investigates how the lymph node (LN) regulates tumor dormancy, a stage of quiescence responsible for delayed relapse which affects ~20% of metastatic breast cancer patients. Using this latency window as an opportunity for intervention requires an understanding of site-specific dormancy regulation. Although the LN is the most common site of metastasis, very little is known about how it sustains dormant DTCs and or what triggers reawakening. I hypothesize that stable LN endothelia deposit quiescence factors which are lost when the stable niche is disturbed during inflammation. This proposal combines animal studies, novel models of the LN microvascular niche (MVN), and intravital imaging to identify LN molecules that contribute to DTC quiescence and reawakening. ECM proteomics identified candidate quiescent factors including HSPG4, LOXL1, and TINAGL1 which will be validated in the LN MVNs. Candidates will be functionally tested in the LN MVNs and in vivo. Further, acute inflammation will be used to trigger dormant DTC reawakening in mouse models and by intravital imaging to see whether DTCs “wake up” when their niche is activated. These studies will provide the first mechanistic understanding of how the LN promotes tumor dormancy and demonstrate whether destabilizing the niche through inflammation is sufficient to wake dormant tumor cells up. In the K00 phase, I propose to investigate route of dissemination as a selective force that enriches metastasis-competent populations of tumor cells. Lymphatics are not only less hostile than blood circulation, but present an opportunity for immune escape as LN LEC induce peripheral tolerance in the T cell repertoire. LN LEC-mediated deletion of tumor-specific T cells27 may grant a survival advantage to lymph- exposed DTCs, priming them for immune escape. Metastatic advantage of lymphatic dissemination will be investigated using lymphatic-Cre transgenic mouse models to track dissemination route and metastatic outcome, T cell receptor sequencing to elucidate the systemic effect of local deletion on the peripheral repertoire, and molecular barcoding to track clonality and distribution of DTCs relative to their dissemination route. Understanding how dissemination influences metastasis will help identify which tumor cells are most likely to metastasize for elimination. The proposed aims will shed light on how the LN and lymphatic dissemination instruct metastasis, revealing actionable targets against tumor dormancy and metastatic fitness, provide invaluable experience studying the complex interactions between metastasis and immunity.

项目摘要 转移是癌症最危险的阶段，与绝大多数乳腺癌有关 死亡目前，我们还没有针对转移的治疗方法;因此，了解 在分子、细胞和组织水平上研究转移进展，以开发针对 这种疾病。该提案研究了淋巴结（LN）如何调节肿瘤休眠，这是肿瘤生长的一个阶段。 静止期导致延迟复发，影响约20%的转移性乳腺癌患者。使用 这种延迟窗口作为干预的机会，需要了解特定地点的休眠 调控虽然LN是最常见的转移部位，但对其如何维持淋巴结转移知之甚少。 休眠的DTC和/或触发重新唤醒的原因。我假设稳定的LN内皮存款 当炎症期间稳定的小生境被扰乱时丢失的静止因子。这项建议 结合动物研究，LN微血管生态位（MVN）的新模型和活体成像， LN分子有助于DTC的静止和再唤醒。ECM蛋白质组学鉴定的候选者 静态因素包括HSPG 4、LOXL 1和TINAGL 1，将在LN MVN中进行验证。候选人 将在LN MVN和体内进行功能测试。此外，急性炎症将用于触发 在小鼠模型中休眠的DTC重新唤醒，并通过活体成像观察DTC是否“唤醒”， 他们的生态位被激活了这些研究将提供第一个机制的理解，如何LN促进 肿瘤休眠，并证明是否通过炎症破坏生态位的稳定足以唤醒 休眠的肿瘤细胞在K 00阶段，我建议调查传播途径作为一种选择性的力量 从而增加了肿瘤细胞的转移能力。淋巴不仅没有血液那么敌对 淋巴结淋巴细胞白血病可诱导外周血T细胞免疫耐受， 保留曲目。LN LEC介导的肿瘤特异性T细胞的缺失27可能使淋巴结转移患者的生存优势增加。 暴露在DTC中，使其免疫逃逸。淋巴播散的转移优势将是 研究了使用转基因Cre小鼠模型追踪传播途径和转移 结果，T细胞受体测序，以阐明局部缺失对外周血淋巴细胞的系统性影响。 库和分子条形码，以跟踪DTC的克隆性和分布，与它们的传播有关 路线了解播散如何影响转移将有助于确定哪些肿瘤细胞是最重要的 很可能会转移到体内所提出的目标将阐明LN和淋巴细胞如何在淋巴细胞中表达。 传播指示转移，揭示了针对肿瘤休眠和转移适应性的可操作靶标， 提供了研究转移和免疫之间复杂相互作用的宝贵经验。