Mechanisms associated with organotropic metastasis

与器官转移相关的机制

• 批准号: 10439900
• 负责人: RAGHU KALLURI
• 金额: $ 49.99万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439900
• 关键词: Affect; Blood Vessels; Bone Marrow; Breast Carcinoma; Breast cancer metastasis; Cancer Patient; Cells; Cues; Data; Disease; Distant; Endothelial Cells; Endothelium; Environment; Expression Profiling; Extracellular Matrix; Extravasation; Fibroblasts; Fibrosis; Gene Deletion; Genetically Engineered Mouse; Growth; Growth Factor; Heterogeneity; Homing; Immune; Inflammation; Intercellular Junctions; Kidney; Lead; Liver; Lung; Lymphatic; Malignant Neoplasms; Mediating; Mediator of activation protein; Metastatic Neoplasm to the Kidney; Metastatic Neoplasm to the Lung; Molecular; Molecular Profiling; Molecular Target; Mus; Neoplasm Metastasis; Nonmetastatic; Organ; Production; Proteins; Proteomics; Pulmonary Fibrosis; Reporter; Repression; Role; Route; Seeds; Signal Transduction; Soil; Solid Neoplasm; Source; Testing; Therapeutic; Tissues; Tropism; Vascular Endothelial Cell; Vascular Endothelium; Vascular Permeabilities; cancer cell; cell type; cellular targeting; chemokine; cytokine; design; exosome; experimental study; extracellular vesicles; fibrotic lung; gain of function; insight; kidney fibrosis; lung colonization; malignant breast neoplasm; mouse model; neoplastic cell; new therapeutic target; novel; recruit; single cell analysis; single cell technology; single-cell RNA sequencing; tumor; vascular bed

ABSTRACT Most cancer patients with solid tumors die of metastatic disease and organotropic spread is an understudied aspect of metastasis, for which new insights are urgently required. The prevailing ‘seed and soil’ concept posits that permissive environment in a distant organ (soil) is necessary to support the survival and growth of lurking tumor cells (seeds). Induction of permissive soil in a non-metastatic organ is proposed to re-route metastasis; however, rigorous experimental evidence and mechanistic analyses are lacking. Fibrotic tissue alterations, including inflammation, provide cues for metastasis, together with the signals from bone marrow-derived cells (BMDCs), the tumor secretome, and circulating extracellular vesicles. Our preliminary data suggest organotropic metastasis is not solely dependent on permissive matrix remodeling and BMDCs in the secondary organs, but is also contingent on the disruption of vascular endothelial barrier function imposed by organ-specific vascular junction proteins. Our findings lead to a central hypothesis that ‘vascular heterogeneity functionally contributes to organotropism of metastasis’. We propose studies to unravel the mechanisms, by which distinct fibrotic niches effect organ-specific changes in the vascular beds, leading to organotropic metastasis. Preliminary studies identified angiopoetin-2 (Ang-2) as a putative mediator of lung metastasis. We aim to unravel the mechanisms of Ang-2 dependent tropism to the lung but not the kidney or liver, which also generate high Ang-2 levels in the fibrotic setting. Using single-cell RNAseq and CyTOF, we will determine the cellular and molecular targets of Ang-2 in the pre-metastatic milieu. Preliminary studies show Ang-2 induces vascular leakage in the lung vasculature without impacting kidney or liver vessels, thus directing metastasis to the lung. Exosomes released by the fibrotic organs also increase vascular permeability and metastatic colonization in the lung, without affecting kidney or liver vasculature. Single-cell RNAseq of fibrotic organs, as well as genetically engineered mice (GEMs), will be used to unravel the rate limiting effect of tissue-specific disruption of Ang-2 in breast cancer metastasis. Using novel GEMs generated in the lab, we will trace lineage-specific production of metastasis- inducing exosomes and identify the determinants of organotropism via proteomic analysis. Our preliminary studies show Ang-2 disrupts vascular barriers through repression of claudin-5 that is found exclusively in the lung vasculature, in contrast with the kidney and liver vessels, which present with multiple, redundant endothelial claudins. Integrating mouse models with endothelial-specific deletion of claudin-5 and claudin-5 reporter mice, and with molecular profiling of organ-specific endothelial cells in loss- and gain-of-function experiments, we will elucidate functions of specific claudins in organotropic metastasis. Molecular studies will be performed to identify putative mechanism of Ang-2 mediated suppression of claudin-5 and test whether manipulation of vascular permeability can re-route metastasis regardless of cancer-specific organ predilection. Successful completion of the proposed studies will provide new insights into mechanism of metastasis and therapeutic implications.

抽象的 大多数具有实体瘤的癌症患者死于转移性疾病和有机体扩散是一个知识的方面 迫切需要新见解的转移。普遍的“种子和土壤”概念认为 遥远器官（土壤）中的宽敞环境对于支持潜伏肿瘤的存活和生长是必要的 细胞（种子）。提出了非转移器官中允许土壤的诱导来重新延伸转移。然而， 缺乏严格的实验证据和机理分析。纤维化组织改变，包括 炎症，提供转移的线索，以及来自骨髓衍生细胞（BMDC）的信号， 肿瘤分泌组和细胞外蔬菜。我们的初步数据表明有机转移 不仅取决于二次器官中的允许矩阵重塑和BMDC，但也是 特异性血管连接施加的血管内皮屏障功能的破坏 蛋白质。我们的发现导致了一个中心假设，即“血管异质性在功能上有助于 转移的器官主义。我们提出研究以揭示机制，通过这些机制不同 在血管床中效应器官特异性变化，导致器官转移。初步研究 鉴定出血管生成素2（ANG-2）是肺转移的推定介体。我们旨在揭示 Ang-2依赖性的肺对，而不是肾脏或肝脏，这也会在该肺中产生高的ANG-2水平 纤维化设置。使用单细胞RNASEQ和CYTOF，我们将确定 Ang-2在过去的环境中。初步研究表明，ANG-2诱导肺部血管泄漏 脉管系统没有影响肾脏或肝血管，因此将转移引导到肺部。外泌体发布 通过纤维化器官还增加了肺中的血管渗透性和转移性定植，而不会影响 肾脏或肝脉管系统。纤维化器官的单细胞RNASEQ，以及一般设计的小鼠 （宝石）将用于揭示组织特异性破坏Ang-2在乳腺癌中的限制效果 转移。使用实验室中产生的新宝石，我们将追踪转移的特定谱系特异性产生 诱导的外泌体并通过蛋白质组学分析鉴定有器乐的决定剂。我们的初步 研究表明，Ang-2通过在肺中发现的Claudin-5的反射来破坏血管屏障 脉管系统与肾脏和肝血管相反，这些肾脏和肝血管有多个冗余内皮 克劳丁斯。将鼠标模型与claudin-5和claudin-5记者小鼠的内皮特异性缺失相结合 随着器官特异性内皮细胞在损失和功能获得实验中的分子分析，我们将 阐明特定claudins在器官转移中的功能。将进行分子研究以识别 ANG-2介导的抑制Claudin-5的假定机制，并测试是否对血管操纵 无论癌症特异性器官的预测如何，渗透性​​都可以重新延伸转移。成功完成 拟议的研究将为转移机制和治疗意义提供新的见解。