Mechanisms associated with organotropic metastasis

与器官转移相关的机制

• 批准号: 10532826
• 负责人: RAGHU KALLURI
• 金额: $ 6.38万
• 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/10532826
• 关键词: Biological Models; Blood Vessels; Cancer Patient; Cessation of life; Collagen Type I; Data; Disease; Distant; Endothelium; Environment; Extracellular Matrix; Fibroblasts; Fibrosis; Genetic; Genetically Engineered Mouse; Growth; Heterogeneity; Human body; Immunosuppression; Intercellular Junctions; KRASG12D; Mus; Neoplasm Metastasis; Nonmetastatic; Organ; Play; Proteins; Role; Route; Seeds; Soil; Solid Neoplasm; Tissues; Transgenic Mice; Vascular Endothelial Cell; cancer cell; insight; malignant breast neoplasm; mouse model; neoplastic cell; novel; parent grant; tumor; tumor microenvironment; tumor progression; 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. Our preliminary data suggest organotropic metastasis is not solely dependent on the permissive metastatic extracellular matrix (ECM) remodeling and BMDCs in the secondary organs but is also controlled by the vascular endothelial cell junction proteins and their ability to maintain barrier function. Our preliminary studies suggest endothelial barriers guide organotropic spread of metastasis. Our central hypothesis for this proposal is `vascular heterogeneity functionally contributes to organotropic metastasis.' We demonstrate organ-specific vascular diversity may play a role in organotropic metastasis. Here we propose studies to unravel the mechanisms by which tissue fibrosis influences organ-specific changes in the vascular beds, leading to organotropic metastasis associated with breast cancer. The studies from our group established a variety of novel transgenic mouse models and identified the functional roles of type I collagen (Col1), the most abundant protein in the human body, the tumor microenvironment, and fibrotic tissues. The studies from our group generated two novel genetically engineered mouse model (GEMM) systems. In specific, KPPF;Col1smaKO (FSF-KrasG12D/+;Trp53frt/frt;Pdx1-Flp;SMA- Cre;Col1a1loxP/loxP) mouse model allows genetic deletion of Col1 in αSMA+ fibroblasts in the autochthonous PDAC background. Col1 deletion in fibroblasts accelerates tumor progression and immunosuppression, leading to shortened overall survival. In comparison, KPPC (LSL-KrasG12D/+;Trp53loxP/loxP;Pdx1- Cre;Col1a1loxP/loxP) mice mouse model allows genetic deletion of Col1 in cancer cells in similar autochthonous PDAC background. Col1 deletion in fibroblasts delays tumor progression and alleviates immunosuppression, leading to prolonged overall survival. Mechanistic studies revealed that fibroblast-derived Col1 is normal Col1 heterotrimers composed of 1 and 2 chains. In contrast, cancer cell-derived Col1 is a unique Col1 homotrimers composed of only 1 chains. In this study, we will further examine the effects of Col1 subtypes (homotrimers versus heterotrimers) on cancer cell invasiveness and metastasis.

抽象的 大多数患有实体瘤的癌症患者死于转移性疾病和有机体扩散是一种理解 迫切需要新见解的转移方面。普遍的“种子和土壤”概念提出 遥远器官（土壤）中的宽容环境对于支持潜伏的生存和生长是必要的 肿瘤细胞（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。 但是，缺乏严格的实验证据和机理分析。我们的初步数据暗示 有机体转移不仅取决于宽松的转移性细胞外基质（ECM） 次生器官中的重塑和BMDC，但也由血管内皮细胞连接控制 蛋白质及其维持屏障功能的能力。我们的初步研究建议内皮屏障指南 转移的器官传播。我们对该提议的中心假设是`v血管异质性 在功能上有助于器官转移。”我们证明有机特异性血管多样性可能会发挥作用 在器官转移中的作用。在这里，我们提出的研究以揭示组织纤维化的机制 影响器官特异性变化的血管床的变化，导致有机体转移 乳腺癌。我们小组的研究建立了各种新型的转基因小鼠模型， 确定了I型胶原蛋白（COL1）的功能作用，该蛋白质中最丰富的蛋白质，肿瘤 微环境和纤维化组织。我们小组的研究产生了两种一般设计的小说 鼠标模型（GEMM）系统。特定于kppf; col1smako（fsf-krasg12d/+; trp53frt/frt; pdx1-flp;Sma-- Cre; col1a1loxp/loxp）小鼠模型允许自围候中αSMA+成纤维细胞中Col1的遗传缺失 PDAC背景。成纤维细胞中的COL1缺失会加速肿瘤进展和免疫抑制， 导致总体生存缩短。相比之下，KPPC（lsl-krasg12d/+; trp53loxp/loxp; pdx1-- Cre; col1a1loxp/loxp）小鼠小鼠模型允许在相似自节体中癌细胞中Col1的遗传缺失 PDAC背景。成纤维细胞中的COL1缺失延迟肿瘤进展并减轻免疫抑制， 导致整体生存时间长。机械研究表明，成纤维细胞衍生的COL1是正常的COL1 由1和2链组成的异三聚体。相反，癌细胞衍生的COL1是独特的COL1 仅由1链组成的同构体。在这项研究中，我们将进一步研究Col1亚型的影响 （同构体与异聚体）在癌细胞的侵袭性和转移方面。