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：
10818834
负责人：
RENATO V. IOZZO
金额：
$ 6.18万
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/10818834
关键词：
AMP-activated protein kinase kinase 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 Eating Endothelial Cells Endothelium Enzymes Exons Female Fibroblast Growth Factor Receptors Funding GADD45A gene 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 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.

女性死亡率中最主要的是侵袭性乳腺癌的发生、进展和转移。这肿瘤细胞与肿瘤微环境之间的双向通讯，提供氧气和营养物质，对于促进不受控制的致瘤性发展、异常发展至关重要新生血管形成和广泛转移。因此，更好地理解嵌入的线索和可溶性的这两个隔间之间交换的信息对于加深我们对以下领域的了解将是非常宝贵的：癌症的病理学并可靠地预测临床结果。我们的中心假设是内皮素，基底膜聚糖的蛋白水解片段，多结构域硫酸乙酰肝素蛋白聚糖，利用双受体拮抗作用来阻止内皮细胞参与肿瘤血管生成。这个工作假设是基于一个有影响力和有前途的工作，所有这些工作都是在这笔赠款的赞助。我们发现：[a] Endorepellin 同时以高亲和力连接， VEGFR2 和 2 两种受体的结合强调了内皮素在靶向方面的精致敏感性和特异性内皮细胞。 [b] Endorepellin 触发 VEGFR2 和 2 1 整合素的共内化，同时激活 SHP-1 酪氨酸磷酸酶并减弱 VEGFA 信号传导。 [c] 内皮素诱导通过调节 Beclin 1、LC3 和 p62 表达以 Peg3 依赖性方式实现内皮细胞自噬，处理和细胞定位。 [d] Endorepellin 引起能量传感器激酶的长期激活 AMPK ，与能量水平无关。事实上，这个规定被认为是非规范的 AMPK 磷酸化发生在营养丰富的条件下。 [e] AMPK 下游，内皮素诱发内皮细胞中的自噬通量在机制上与 mTOR 抑制剂 Torin 1 相似。这些惊人的研究结果表明，长期且持续的自噬是内皮素发挥作用的一种新机制。促进血管抑制，与营养剥夺无关。基于这些发现，我们计划： [1] 阐明内皮素诱发内皮细胞应激、自噬和线粒体自噬的机制。 [2] 揭示内皮素诱导 HAS2 自噬抑制的机制。 [3] 生成新的肿瘤发生小鼠模型来解释促自噬和抗血管生成程序由内皮素激活。这些一致的研究目标将使我们能够转化我们通过高度创新的鼠标获得的发现基质自噬模型转化为临床相关范例。内皮素诱导的发现双受体拮抗下游的内皮细胞自噬将带来新的治疗进展积极诱导肿瘤微环境中的自噬来对抗这种毁灭性的疾病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Progranulin and EGFR modulate receptor-like tyrosine kinase sorting and stability in mesothelioma cells.

颗粒体蛋白前体和 EGFR 调节间皮瘤细胞中的受体样酪氨酸激酶分选和稳定性。

DOI：
发表时间：
2023-08-01
期刊：
影响因子：
0
作者：
Ventura, Elisa;Belfiore, Antonino;Iozzo, Renato V;Giordano, Antonio;Morrione, Andrea
通讯作者：
Morrione, Andrea

A role for decorin in improving motor deficits after traumatic brain injury.

核心蛋白聚糖在改善脑外伤后运动缺陷中的作用。

DOI：
10.1016/j.matbio.2023.12.005
发表时间：
2023-12-01
期刊：
Matrix biology : journal of the International Society for Matrix Biology
影响因子：
0
作者：
Kaori Oshima;N. Siddiqui;J. Orfila;Danelle J Carter;Justin Laing;Xiaorui Han;I. Zakharevich
通讯作者：
I. Zakharevich