Tumor Endothelial Cell Regulation of Pro-Metastatic Fibrin Matrices

项目摘要 肺癌和三阴性乳腺癌(TNBCs)是美国癌症相关死亡的主要原因。 高死亡率在很大程度上是由于它们有快速进展和转移的倾向。虽然靶向治疗 肺腺癌提高了总体生存率，在肺鳞癌(LUSC)中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，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/免疫是如何 肿瘤微环境(TME)中的利基环境促进了LUSC，而TNBC将使我们能够在此基础上进一步发展 预付款。我们的团队最近证明了LUSC和TNBC促进肿瘤生长和转移 通过纤维蛋白重塑的趋同(《自然通讯》，2018；J临床研究，2019年)和 内皮细胞创伤修复程序的激活(致癌基因，2019)。纤维蛋白(原)能逃脱渗漏的肿瘤 血管内皮细胞(TECs)作为肿瘤细胞运动的支架，为肿瘤创造临时基质 进步。利用高度集成的生物信息学和新的LUSC模型，我们最近发现CCL2- FXIIIA(FXIIIA)介导的表达炎性单核细胞(IMS)的募集促进纤维蛋白交叉 LUSC中的连接、转移和低存活率。我们还发现，TEC异质性(TECH)引导纤维蛋白 通过转化生长因子β/miR-30c/PAI-1信号轴-具有高水平纤溶抑制物的TECs积聚， 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结合蛋白颤动之间的次要联系 (QKI)，富含TECs，促进肿瘤血管生成。沉默TECs中的QKI抑制萌发 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 CXCL12介导的CXCR4 IMS的隔离启动纤维蛋白交联。基于这些集体新闻 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，并 然而，转移，CXCL12介导的FXIIIA IMS滞留促进纤维蛋白重塑和反弹 血管生成。此外，我们提出(Ii)技术推动了异常的和持久的血管周围的形成 纤维蛋白支架通过转化生长因子β/miR-30c/PAI-1在喉癌和肿瘤细胞中的表达。这样做的目的是 建议阐明纤维蛋白重塑和肿瘤进展如何依赖于异型关系。 TEC和IMS之间的差异，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.