How Circulating Melanoma Cells Usurp the Leukocyte Transmigration Mechanism for Successful Metastasis

循环黑色素瘤细胞如何篡夺白细胞迁移机制以实现成功转移

基本信息

  • 批准号:
    10608160
  • 负责人:
  • 金额:
    $ 41.74万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-01 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

Most deaths from solid tumors are due to metastases—cancer cells breaking off the primary tumor, traveling to distant parts of the body and establishing new growths there. Patients with cancer shed millions of circulating tumor cells (CTCs) into their bloodstream every day. There is a good deal known about how malignant cells break away from the primary tumor and move through connective tissue into lymphatics and blood vessels. Almost all CTCs die in the vasculature or are eliminated by the body’s inflammatory response. However, those tumor cells that manage to extravasate out of the bloodstream and into tissues have the potential to grow as metastatic colonies that spread the cancer far beyond the primary site. Unfortunately, there is almost nothing known about this step. We have evidence that a substantial fraction of melanoma cells can cross blood vessels using the same molecular machinery that white blood cells do. Leukocytes migrate across endothelial cells (EC) without increasing vascular permeability or inducing tissue damage. They do this through a series of molecular interactions with molecules on the endothelial cells that recruit membrane from a perijunctional organelle called the lateral border recycling compartment (LBRC). Membrane from the LBRC increases the surface area of the junction allowing leukocytes to pass across without harming the EC; the junction barriers remain tight and there is no exposure of the basement membrane. Our preliminary data show that a major fraction (1/3 to ½ ) of melanoma cells can migrate across endothelial cells. Moreover, we can selectively block their transmigration in vitro and in vivo using a novel cell-permeable inhibitor of LBRC movement. Strikingly, the number of metastatic colonies that develop in mice treated with the inhibitor is disproportionately lower than the degree to which extravasation is blocked. This suggests that those melanoma cells that transmigrate using the LBRC have a survival advantage. We hypothesize that blocking recruitment of the LBRC by melanoma cells would be an efficient way to block successful metastases. We will test our hypothesis in mechanistic studies that determine the extent to which different driver mutations affect the ability of melanoma cell lines and malignant melanoma cells derived from patients recruit the LBRC to transmigrate (Aim I). We will use our novel selective inhibitor of LBRC movement to block metastases of murine melanomas in syngeneic wild-type mice as well metastases from human patient-derived melanoma xenografts (PDX) in NSG mice (Aim II). Melanomas do not express the molecules used by leukocytes to recruit the LBRC; Aim III will determine the mechanisms used by tumor cells to recruit the LBRC. This will reveal therapeutic targets for selectively blocking metastasis without inhibiting the immune response. Preliminary data show that inhibitors of reactive oxygen species as well as endothelial EP4 receptors block melanoma transmigration in vitro, suggesting that ROS and PGE2 secreted by melanomas recruits the LBRC. We will test whether metastases from murine melanoma and PDX are reduced in inducible endothelial cell-specific TRPM2 or EP4 knockout mice.
大多数实体瘤的死亡是由于转移——癌细胞从原发肿瘤中脱落,

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

William A Muller其他文献

William A Muller的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('William A Muller', 18)}}的其他基金

Transendothelial Migration of Leukocytes: Developing New Paradigms in Health and Disease
白细胞跨内皮迁移:开发健康和疾病的新范式
  • 批准号:
    10371033
  • 财政年份:
    2021
  • 资助金额:
    $ 41.74万
  • 项目类别:
Transendothelial Migration of Leukocytes: Developing New Paradigms in Health and Disease
白细胞跨内皮迁移:开发健康和疾病的新范式
  • 批准号:
    10570168
  • 财政年份:
    2021
  • 资助金额:
    $ 41.74万
  • 项目类别:
How Circulating Melanoma Cells Usurp the Leukocyte Transmigration Mechanism for Successful Metastasis
循环黑色素瘤细胞如何篡夺白细胞迁移机制以实现成功转移
  • 批准号:
    9901494
  • 财政年份:
    2019
  • 资助金额:
    $ 41.74万
  • 项目类别:
How Circulating Melanoma Cells Usurp the Leukocyte Transmigration Mechanism for Successful Metastasis
循环黑色素瘤细胞如何篡夺白细胞迁移机制以实现成功转移
  • 批准号:
    10380853
  • 财政年份:
    2019
  • 资助金额:
    $ 41.74万
  • 项目类别:
Identifying the membrane proteins of the LBRC, a key regulator of inflammation
鉴定 LBRC 的膜蛋白(炎症的关键调节因子)
  • 批准号:
    8072018
  • 财政年份:
    2010
  • 资助金额:
    $ 41.74万
  • 项目类别:
Identifying the membrane proteins of the LBRC, a key regulator of inflammation
鉴定 LBRC 的膜蛋白(炎症的关键调节因子)
  • 批准号:
    7872115
  • 财政年份:
    2010
  • 资助金额:
    $ 41.74万
  • 项目类别:
Differentiation and fate of monocytes in atherosclerosis
动脉粥样硬化中单核细胞的分化和命运
  • 批准号:
    7406108
  • 财政年份:
    2007
  • 资助金额:
    $ 41.74万
  • 项目类别:
PECAM-INDEPENDENT TRANSENDOTHELIAL MIGRATION
PECAM 独立的跨内皮迁移
  • 批准号:
    6088605
  • 财政年份:
    2000
  • 资助金额:
    $ 41.74万
  • 项目类别:
Beyond PECAM: Mechanisms of Transendothelial Migration
超越 PECAM:跨内皮迁移机制
  • 批准号:
    8284380
  • 财政年份:
    2000
  • 资助金额:
    $ 41.74万
  • 项目类别:
Beyond PECAM: Mechanisms of Transendothelial Migration
超越 PECAM:跨内皮迁移机制
  • 批准号:
    7408548
  • 财政年份:
    2000
  • 资助金额:
    $ 41.74万
  • 项目类别:

相似海外基金

Double Incorporation of Non-Canonical Amino Acids in an Animal and its Application for Precise and Independent Optical Control of Two Target Genes
动物体内非规范氨基酸的双重掺入及其在两个靶基因精确独立光学控制中的应用
  • 批准号:
    BB/Y006380/1
  • 财政年份:
    2024
  • 资助金额:
    $ 41.74万
  • 项目类别:
    Research Grant
Quantifying L-amino acids in Ryugu to constrain the source of L-amino acids in life on Earth
量化 Ryugu 中的 L-氨基酸以限制地球生命中 L-氨基酸的来源
  • 批准号:
    24K17112
  • 财政年份:
    2024
  • 资助金额:
    $ 41.74万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Molecular recognition and enantioselective reaction of amino acids
氨基酸的分子识别和对映选择性反应
  • 批准号:
    23K04668
  • 财政年份:
    2023
  • 资助金额:
    $ 41.74万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Basic research toward therapeutic strategies for stress-induced chronic pain with non-natural amino acids
非天然氨基酸治疗应激性慢性疼痛策略的基础研究
  • 批准号:
    23K06918
  • 财政年份:
    2023
  • 资助金额:
    $ 41.74万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular mechanisms how arrestins that modulate localization of glucose transporters are phosphorylated in response to amino acids
调节葡萄糖转运蛋白定位的抑制蛋白如何响应氨基酸而被磷酸化的分子机制
  • 批准号:
    23K05758
  • 财政年份:
    2023
  • 资助金额:
    $ 41.74万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Design and Synthesis of Fluorescent Amino Acids: Novel Tools for Biological Imaging
荧光氨基酸的设计与合成:生物成像的新工具
  • 批准号:
    2888395
  • 财政年份:
    2023
  • 资助金额:
    $ 41.74万
  • 项目类别:
    Studentship
Collaborative Research: RUI: Elucidating Design Rules for non-NRPS Incorporation of Amino Acids on Polyketide Scaffolds
合作研究:RUI:阐明聚酮化合物支架上非 NRPS 氨基酸掺入的设计规则
  • 批准号:
    2300890
  • 财政年份:
    2023
  • 资助金额:
    $ 41.74万
  • 项目类别:
    Continuing Grant
Structurally engineered N-acyl amino acids for the treatment of NASH
用于治疗 NASH 的结构工程 N-酰基氨基酸
  • 批准号:
    10761044
  • 财政年份:
    2023
  • 资助金额:
    $ 41.74万
  • 项目类别:
Lifestyle, branched-chain amino acids, and cardiovascular risk factors: a randomized trial
生活方式、支链氨基酸和心血管危险因素:一项随机试验
  • 批准号:
    10728925
  • 财政年份:
    2023
  • 资助金额:
    $ 41.74万
  • 项目类别:
Single-molecule protein sequencing by barcoding of N-terminal amino acids
通过 N 端氨基酸条形码进行单分子蛋白质测序
  • 批准号:
    10757309
  • 财政年份:
    2023
  • 资助金额:
    $ 41.74万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了