Proteoglycan regulation of tumor angiogenesis and endothelial cell autophagy

蛋白多糖对肿瘤血管生成和内皮细胞自噬的调节

基本信息

批准号：
10634656
负责人：
RENATO V. IOZZO
金额：
$ 37.79万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634656
关键词：
Affect Affinity Allografting Angiogenesis Inhibitors Angiogenic Factor Angiostatic Proteins Autophagocytosis Binding Biological Biology Breast Cancer cell line Breast Carcinoma C-terminal Cancer Biology Cells Cellular Stress Chemicals Communication Complex Core Protein Cues Development Disease EIF-2alpha Eating Endothelial Cells Endothelium Enzymes Exons Female Fibroblast Growth Factor Receptors Funding Gene Targeting Genetic Genetic Transcription Grant Growth HAS2 gene Heparan Sulfate Proteoglycan Hyaluronan Immunologics In Vitro Integrins KDR gene Knowledge Laboratories Ligation Link Malignant Neoplasms Mediating Methodology Modality Modeling Molecular Mus Mutate Names Neoplasm Metastasis Nutrient Oxygen PTPN6 gene Parents Parkin Pathway interactions Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Protein Tyrosine Phosphatase Proteins Proteoglycan Recombinants Regulation Research Role Second Primary Cancers Sensitivity and Specificity Signal Transduction Specificity Stromal Cells Tamoxifen Technology Testing Time Transgenic Mice Translating Tumor Angiogenesis VEGFA gene Vascular Endothelium Vascularization Work Zebrafish adhesion receptor aggressive breast cancer angiogenesis antagonist attenuation cancer cell cell behavior cellular engineering clinically relevant combat confocal imaging experimental study genetic signature in vivo inducible Cre inhibitor innovation interdisciplinary approach mTOR Inhibitor mTOR inhibition malignant breast neoplasm mortality mouse model mutant nano-string neoplastic cell neovascularization novel novel therapeutics nutrient deprivation overexpression paracrine perlecan predict clinical outcome programs promoter receptor sensor transcriptome transcriptomics tumor tumor microenvironment tumor progression tumorigenesis tumorigenic ultra high resolution

项目摘要

Chief among female mortality is the development, progression, and metastasis of aggressive breast cancer. The bidirectional communication between the neoplastic cells and the tumor microenvironment, which supplies oxygen and nutrients, is essential for promoting unchecked tumorigenic development, aberrant neovascularization, and widespread metastasis. Thus, a better understanding of embedded cues and soluble messages exchanged between these two compartments will prove invaluable for furthering our knowledge of the pathobiology of cancer and for reliably predicting clinical outcomes. Our central hypothesis is that endorepellin, a proteolytic fragment of perlecan, a multi-domain heparan sulfate proteoglycan, exploits a dual-receptor antagonism to preclude endothelial cells from participating in tumor angiogenesis. This working hypothesis is based on an impactful and promising body of work all generated under the auspices of this grant. We discovered that: [a] Endorepellin simultaneously ligates, with high affinity, VEGFR2 and the 21 integrin thereby constituting the molecular basis of “dual receptor antagonism”. Engagement of both receptors underscores the exquisite sensitivity and specificity of endorepellin in targeting the endothelia. [b] Endorepellin triggers co-internalization of VEGFR2 and 21 integrin with concurrent activation of the SHP-1 tyrosine phosphatase and attenuation of VEGFA signaling. [c] Endorepellin induces endothelial cell autophagy in a Peg3-dependent manner by modulating Beclin 1, LC3, and p62 expression, processing, and cellular localization. [d] Endorepellin evokes protracted activation of the energy-sensor kinase AMPK, irrespective of energy levels. Indeed, this regulation is considered non-canonical as AMPK phosphorylation occurred under nutrient-enriched conditions. [e] Downstream of AMPK, endorepellin evokes autophagic flux in endothelial cells that mechanistically parallels the mTOR inhibitor, Torin 1. These striking findings demonstrate that protracted and sustained autophagy is a novel mechanism by which endorepellin promotes angiostasis, independent of nutrient deprivation. Based on these discoveries, we plan to: [1] Elucidate the mechanism of endorepellin-evoked endothelial cell stress, autophagy and mitophagy. [2] Unravel the mechanism by which endorepellin induces autophagic suppression of HAS2. [3] Generate novel mouse models of tumorigenesis to explain the pro-autophagic and anti-angiogenic programs activated by endorepellin. These concerted research aims will enable us to translate our findings, procured with highly innovative mouse models of stromal autophagy, into clinically relevant paradigms. The discovery of endorepellin-induced endothelial cell autophagy downstream of dual receptor antagonism will lead to new therapeutic advances that actively induce autophagy within the tumor microenvironment to combat this devastating disease.

女性凡人的主要是发展肿瘤细胞与肿瘤微环境之间的双向通信，该环境提供氧气和营养，对于促进未检查的肿瘤发育至关重要，异常新生血管和宽度转移。这两个隔间之间交换的消息将证明我们对癌症病理生物学以及可靠地预测临床结果。我们的中心假设是内核蛋白，一种多域硫酸乙酰肝素的蛋白水解片段蛋白聚糖，利用双受体拮抗作用，使内皮细胞无法参与肿瘤血管生成。这项赠款的主持人。 VEGFR2和211整联蛋白所构成的“双重受体拮抗作用”的分子基础。两种受体的参与强调了靶向靶向的精致敏感性和特异性内皮。 SHP-1酪氨酸磷酸盐的激活和VEGFA信号的注意。内皮细胞细胞以PEG3依赖性方式自噬，通过调节Beclin 1，LC3和P62表达，处理和细胞定位。 Ampk，无论能量水平是否，该法规都被认为是非典型的磷酸化发生在养分 - 富裕条件下。在机械上与MTOR抑制剂合同的内皮细胞中的自噬通量，Torin 1。调查结果表明，长期和持续的自噬是一种新型机制根据这些发现，促进了与营养剥夺无关的血管疾病。 [1]阐明了内螺旋蛋白诱发的触地式触发细胞应激，自噬和线粒体的机制。 [2]揭示了内核诱导诱导自噬抑制HAS2的机制。 [3]生成新型的肿瘤发生小鼠模型，以解释亲噬型和Andi -Ngiogenic程序由内核蛋白激活。这些协调的研究目的将使我们能够翻译我们的发现，并以高度创新的鼠标购买基质自噬的模型，临床相关的范例。内皮细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞和细胞t t 积极诱导肿瘤微环境中的Itophapy，以打击这种毁灭性疾病。