Tumor Endothelial Cell Regulation of Pro-Metastatic Fibrin Matrices

项目摘要 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它们倾向于迅速进展和转移。虽然靶向治疗 肺腺癌的总生存率有所提高，肺鳞癌（LUSC）的进展相似 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/或免疫检查点阻断都是有效的。 血管生成抑制剂改善疾病控制。因此，更全面地了解血管/免疫 肿瘤微环境（TME）内的小生境促进LUSC和TNBC将使我们能够在这些基础上建立 预付款。我们的团队最近证明LUSC和TNBC促进肿瘤生长和转移 通过对纤维蛋白重塑的融合（Nature Communications，2018; J Clinical Investigation，2019）， 激活内皮细胞伤口愈合程序（Oncogene，2019）。逃避渗漏肿瘤的纤维素（原） 内皮细胞（TEC）作为肿瘤细胞运动的支架，并为肿瘤细胞提供临时基质， 进展使用高度集成的生物信息学和新的LUSC模型，我们最近发现CCL 2- 表达因子XIIIA（FXIIIA）的炎性单核细胞（IM）介导的募集促进纤维蛋白交叉， 在LUSC中的连接、转移和低生存率。我们还发现TEC异质性（TECH）指导纤维蛋白 通过TGFβ/miR-30 c/派-1信号传导轴-具有高水平纤维蛋白溶解抑制剂的TEC积累， 派-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之间的第二种联系 (QKI)其富含TEC并驱动肿瘤血管生成。沉默TEC中的QKI抑制发芽 血管生成和转移，但微血管密度（MVD）矛盾地增加;我们认为这是由于 CXCL 12介导的CXCR 4 + IM的隔离，其启动纤维蛋白交联。基于这些新的集体 根据我们小组的见解，我们假设（i）抑制TEC QKI最初阻断肿瘤血管生成， 然而，在转移中，CXCL 12介导的FXIIIA+ IM的保留促进纤维蛋白重塑和反弹， 血管生成此外，我们提出（ii）TECH驱动异常和持续性血管周围血管的形成， 通过TGFβ/miR-30 c/派-1表达谱，在LUSC和TNBC中的纤维蛋白支架中观察。的目的 建议是阐明纤维蛋白重塑和肿瘤进展如何依赖于异型关系 以及TME内TEC之间的异质性。

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.