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: 10356164
• 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/10356164
• 关键词: Angiogenesis Inhibitors; Bioinformatics; Blood Vessels; Breast Cancer Model; CCL2 gene; CXCL12 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; Pharmacology; Plasminogen Activator Inhibitor 1; RNA-Binding Proteins; Regulation; Reporter; Reporting; Role; Signal Transduction; Squamous Cell Lung Carcinoma; Transforming Growth Factor beta; Tumor Angiogenesis; angiogenesis; base; 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; programs; recruit; scaffold; support network; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; ultrasound; 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.

项目概要 肺癌和三阴性乳腺癌 (TNBC) 是美国癌症相关死亡的主要原因 高死亡率主要是由于其快速进展和转移的倾向。靶向治疗的同时 肺腺癌的总体生存率有所提高，肺鳞癌 (LUSC) 也取得了类似的进展 和TNBC一直停滞不前。然而，对于这两种癌症类型，免疫检查点阻断和/或 血管生成抑制剂可改善疾病控制。因此，更全面地了解血管/免疫如何 肿瘤微环境 (TME) 内的利基促进了 LUSC，而 TNBC 将使我们能够在此基础上再接再厉 进步。我们的团队最近证明 LUSC 和 TNBC 促进肿瘤生长和转移 通过纤维蛋白重塑的融合（Nature Communications，2018；J Clinical Investigation，2019）和 激活内皮细胞伤口愈合程序（Oncogene，2019）。逃离渗漏肿瘤的纤维蛋白（原） 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。利用高度集成的生物信息学和新颖的 LUSC 模型，我们最近发现 CCL2- 介导表达因子 XIIIA (FXIIIA) 的炎症单核细胞 (IM) 的募集促进纤维蛋白交叉 LUSC 中的连接、转移和不良生存。我们还发现 TEC 异质性 (TECH) 指导纤维蛋白 通过 TGFβ/miR-30c/PAI-1 信号轴积累 - TEC 具有高水平的纤溶抑制剂， PAI-1，增加血管周围纤维蛋白网络，支持萌芽血管生成和肿瘤进展。我们 还发现了纤维蛋白重塑和 RNA 结合蛋白 Quaking 之间的次要联系 (QKI) 富含 TEC，可促进肿瘤血管生成。沉默 TEC 中的 QKI 可抑制发芽 血管生成和转移，但微血管密度（MVD）反而增加；我们认为这是由于 CXCL12 介导的 CXCR4+ IM 隔离，启动纤维蛋白交联。基于这些集体新 根据我们小组的见解，我们假设 (i) 抑制 TEC QKI 最初会阻止肿瘤血管生成， 然而，在转移过程中，CXCL12 介导的 FXIIIA+ IM 保留可促进纤维蛋白重塑和反弹 血管生成。此外，我们建议 (ii) 技术驱动异常和持续性血管周围血管的形成 通过 TGFβ/miR-30c/PAI-1 表达谱研究 LUSC 和 TNBC 中的纤维蛋白支架。此举的目的 提议是阐明纤维蛋白重塑和肿瘤进展如何依赖于异型关系 TEC 和 IM 之间的差异，以及 TME 内 TEC 之间的异质性。