Tumor Endothelial Cell Regulation of Pro-Metastatic Fibrin Matrices

肿瘤内皮细胞对促转移纤维蛋白基质的调节

• 批准号: 10573196
• 负责人: Andrew Carl Dudley
• 金额: $ 56.85万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573196
• 关键词: Angiogenesis Inhibitors; Binding; Bioinformatics; Blood Vessels; Breast Cancer Model; CCL2 gene; CXCR4 gene; Cancer Etiology; Cells; Cessation of life; Characteristics; Communication; Deposition; Disease; Disease Progression; Endothelial Cells; Extracellular Matrix; Factor XIIIa; Fibrin; Fibrinolysis; Genetic; Heterogeneity; Hydrogels; Immune; Inflammatory; Kinetics; Lung; Lung Adenocarcinoma; Mediating; Microfluidics; Modeling; Molecular Probes; Mus; Nature; Neoplasm Metastasis; Oncogenes; Plasminogen Activator Inhibitor 1; RNA-Binding Proteins; Regulation; Reporter; Reporting; Role; Signal Transduction; Squamous Cell Lung Carcinoma; Stromal Cell-Derived Factor 1; Transforming Growth Factor beta; Tumor Angiogenesis; Tumor Promotion; angiogenesis; cancer type; cell motility; clinical investigation; crosslink; density; disorder control; extracellular vesicles; human disease; immune checkpoint blockade; improved; in vivo; indexing; inhibitor; insight; monocyte; mortality; mouse model; neoplastic cell; novel; pharmacologic; programs; recruit; scaffold; support network; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; ultrasound; vascular factor; wound healing; Angiogenesis Inhibitors; Binding; Bioinformatics; Blood Vessels; Breast Cancer Model; CCL2 gene; CXCR4 gene; Cancer Etiology; Cells; Cessation of life; Characteristics; Communication; Deposition; Disease; Disease Progression; Endothelial Cells; Extracellular Matrix; Factor XIIIa; Fibrin; Fibrinolysis; Genetic; Heterogeneity; Hydrogels; Immune; Inflammatory; Kinetics; Lung; Lung Adenocarcinoma; Mediating; Microfluidics; Modeling; Molecular Probes; Mus; Nature; Neoplasm Metastasis; Oncogenes; Plasminogen Activator Inhibitor 1; RNA-Binding Proteins; Regulation; Reporter; Reporting; Role; Signal Transduction; Squamous Cell Lung Carcinoma; Stromal Cell-Derived Factor 1; Transforming Growth Factor beta; Tumor Angiogenesis; Tumor Promotion; angiogenesis; cancer type; cell motility; clinical investigation; crosslink; density; disorder control; extracellular vesicles; human disease; immune checkpoint blockade; improved; in vivo; indexing; inhibitor; insight; monocyte; mortality; mouse model; neoplastic cell; novel; pharmacologic; programs; recruit; scaffold; support network; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; ultrasound; vascular factor; wound healing

Project Summary Lung and triple-negative breast cancers (TNBCs) are leading causes of cancer-related deaths in the U.S. This high mortality rate is largely due to their propensity to rapidly progress and metastasize. While targeted therapies for lung adenocarcinoma have improved overall survival, similar advances in lung squamous carcinoma (LUSC) and TNBC have been stagnant. However, for both cancer types, immune checkpoint blockade and/or angiogenesis inhibitors improves disease control. Thus, a more complete understanding of how vascular/immune niches within the tumor microenvironment (TME) promotes LUSC and TNBC will allow us to build upon these advances. Our teams have recently demonstrated that LUSC and TNBC promote tumor growth and metastases through a convergence on fibrin remodeling (Nature Communications, 2018; J Clinical Investigation, 2019) and activation of endothelial cell wound-healing programs (Oncogene, 2019). Fibrin(ogen) that escapes leaky tumor endothelial cells (TECs) acts as a scaffold for tumor cell motility and creates a provisional matrix for tumor progression. Using highly integrated bioinformatics and novel LUSC models, we recently found that CCL2- mediated recruitment of Factor XIIIA (FXIIIA)-expressing inflammatory monocytes (IMs) promotes fibrin cross- linking, metastases and poor survival in LUSC. We also found that TEC heterogeneity (TECH) directs fibrin accumulation through a TGFβ/miR-30c/PAI-1 signaling axis - TECs with high levels of the fibrinolysis inhibitor, PAI-1, increase perivascular fibrin networks that support sprouting angiogenesis and tumor progression. We have also uncovered a secondary connection between fibrin remodeling and the RNA-binding protein Quaking (QKI) which is enriched in TECs and drives tumor angiogenesis. Silencing QKI in TECs inhibits sprouting angiogenesis and metastases, but micro-vessel density (MVD) paradoxically increases; which we posit is due to CXCL12-mediated sequestering of CXCR4+ IMs that initiate fibrin cross-linking. Based on these collective new insights from our groups, we hypothesize that (i) inhibition of TEC QKI initially blocks tumor angiogenesis and metastasis, however, a CXCL12-mediated retention of FXIIIA+ IMs promotes fibrin remodeling and rebound angiogenesis. Additionally, we propose (ii) that TECH drives the formation of aberrant and persistent perivascular fibrin scaffolds in LUSC and TNBC via a spectrum of TGFβ/miR-30c/PAI-1 expression. The objective of this proposal is to elucidate how fibrin remodeling and tumor progression depend on the heterotypic relationships between TECs and IMs, and the heterogeneity amongst TECs within the TME.

项目摘要 在美国，肺和三阴性乳腺癌（TNBC）是与癌症相关死亡的主要原因 高死亡率很大程度上是由于它们倾向于快速发展和转移。而有针对性的疗法 对于肺腺癌的总生存率提高了，肺鳞状癌（LUSC）的进步相似 TNBC一直停滞不前。但是，对于两种癌症类型，免疫切除点封锁和/或 血管生成抑制剂改善疾病控制。这是对如何血管/免疫的更完整的了解 肿瘤微环境（TME）内的壁ni，促进LUSC和TNBC将使我们能够在这些基础上建立 进步。我们的团队最近证明了LUSC和TNBC促进肿瘤的生长和转移 通过纤维蛋白重塑的收敛（自然通讯，2018年； J临床研究，2019年）和 激活内皮细胞世界修复程序（Oncogene，2019年）。纤维蛋白（ogen）逃避漏水的肿瘤 内皮细胞（TEC）充当肿瘤细胞运动的支架，并为肿瘤创建临时基质 进展。使用高度集成的生物信息学和新型LUSC模型，我们最近发现CCL2- 表达炎症单核细胞（IMS）的介导的XIIIA（FXIIIA）因子募集促进纤维蛋白交叉 - 在LUSC中连接，转移和较差的生存率。我们还发现TEC异质性（Tech）指导纤维蛋白 通过TGFβ/miR-30c/pAI-1信号轴积聚，具有高水平的纤维蛋白溶解剂， PAI-1，增加支持发芽血管生成和肿瘤进展的血管周纤维蛋白网络。我们 还发现了纤维蛋白重塑与RNA结合蛋白震颤之间的次要连接 （QKI）富含TEC并驱动肿瘤血管生成。在TEC中沉默的QKI抑制发芽 血管生成和转移，但是微毒剂密度（MVD）矛盾地增加。我们肯定是由于 启动纤维蛋白交联的CXCL1介导的CXCR4+ IMS的隔离。基于这些集体新 我们群体的见解，我们假设（i）抑制TEC QKI最初会阻止肿瘤血管生成和 但是，转移，FXIIIA+ IMS的CXCL12介导的保留促进了纤维蛋白的重塑和反弹 血管生成。此外，我们建议（ii）技术驱动异常和持续性周围的形成 LUSC和TNBC中的纤维蛋白支架通过TGFβ/miR-30c/pAI-1表达的光谱。这个目的 建议是阐明纤维蛋白重塑和肿瘤进展如何依赖异型关系 在TEC和IMS之间，以及TME内TEC之间的异质性。