Defining extracellular vesicle-mediated drug resistance in AML

定义 AML 中细胞外囊泡介导的耐药性

基本信息

批准号：
10011557
负责人：
John Thomas Butler
金额：
$ 5.05万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10011557
关键词：
Abnormal Myeloid Cell Acute Myelocytic Leukemia Adjuvant Adult Affect Apoptosis Automobile Driving Biogenesis Biopsy Bone Marrow Bone Marrow Cells Bone remodeling Cancer Model Cells Chemoprotective Agent Child Conditioned Reflex Disease Disease remission Distant Drug resistance Environment Exhibits Extracellular Space Genes Goals Growth Factor Hematopoiesis Leukemic Cell Malignant Neoplasms Mediating Membrane Mesenchymal Stem Cells Modeling Multivesicular Body Mus Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiological Play Probability Process Proteins Receptor Signaling Relapse Resistance Role Signal Transduction Solid Neoplasm Stress Stromal Cells Testing Toxic effect Up-Regulation Vesicle acute myeloid leukemia cell bone bone morphogenic protein cancer drug resistance cancer survival cell type chemotherapy endoplasmic reticulum stress exosome extracellular vesicles improved in vivo inhibitor/antagonist leukemia metaplastic cell transformation mouse model new therapeutic target novel therapeutic intervention novel therapeutics osteogenic osteoprogenitor cell overexpression prevent receptor response stem cells therapeutic target tool trafficking transmission process tumor initiation tumor microenvironment tumor progression uptake vesicular release

项目摘要

Project Summary Acute Myelogenous Leukemia (AML) is an aggressive, genetically heterogeneous cancer—affecting both children and adults—that arises from abnormal myeloid cells in the bone marrow (BM). While many patients achieve remission following induction chemotherapy, the 5-year survival remains a dismal 25% due to relapse with increased resistance to cancer drugs. AML remodels the BM microenvironment, in part by releasing membrane-bound extracellular vesicles (EVs) that dysregulate recipient cells. We have found that EVs transfer endoplasmic reticulum-stress to stromal cells, leading to cell type-specific phenotypic changes that alter the cellular composition of the BM. Interestingly, these EVs were also found to contain bone morphorgenic proteins (BMP)—potent growth factors implicated in drug resistance and cancer progression. Currently little is known about how EV-mediated transmission of ER-stress and BMPs contribute to forming a chemo-protective niche. Multiple studies have shown that ER-stress can be transmitted between cells in the tumor microenvironment, contributing to drug resistance in solid tumor models. In the context of AML, we have found that EVs alone are sufficient to transmit ER-stress and activate the Unfolded Protein Response (UPR) pathway in recipient stromal cells. In vivo, AML cells exhibit marked UPR due to physiologic stress in the tumor microenvironment. We have found that the upregulation of the UPR pathway coincides with the increased expression and packaging of multiple BMP types onto EVs. Since both UPR and BMPs have been previously implicated in promoting cancer survival and drug resistance, we propose to study the role of EVs in transferring adaptive change to recipient BM cells to form a chemo-protective environment. Additionally, due to the mounting evidence that AML-EVs remodel the BM microenvironment, blocking EV biogenesis has become an obvious therapeutic target for AML. We hypothesize that EV-mediated transmission of Unfolded Protein Response and bone morphogenic proteins promotes adaptive changes contributing to drug resistance in AML, which can be ameliorated by inhibiting the release of EVs. To test this hypothesis, In AIM 1, we will identify the contribution of EV-mediated transmission of ER-stress in promoting chemo-protective changes in both recipient stromal and AML cells, and determine if inhibiting exosome release can prevent these effects. In Aim 2 we will determine how EV-associated BMPs dysregulate stromal cells, and examine the effect of blocking EV-release and BMP-receptor signaling on AML progression. Our long-term goal is to answer long standing questions about how AML cells evade chemotherapy and develop new therapeutic strategies to reduce drug resistance in patients with AML.

项目概要急性髓性白血病 (AML) 是一种侵袭性、遗传异质性癌症，影响儿童和成人——由骨髓 (BM) 中的异常骨髓细胞引起。诱导化疗后达到缓解，但由于复发，5年生存率仍然只有25% AML 部分通过释放癌症药物来重塑 BM 微环境。我们发现膜结合的细胞外囊泡 (EV) 会失调受体细胞。内质网对基质细胞的应激，导致细胞类型特异性表型变化，从而改变 BM 的细胞组成表明，这些 EV 还含有骨形态发生蛋白。 (BMP)——与耐药性和癌症进展有关的有效生长因子目前知之甚少。关于 EV 介导的 ER 应激和 BMP 传播如何有助于形成化疗保护生态位。多项研究表明，内质网应激可以在肿瘤微环境中的细胞之间传递，在 AML 的背景下，我们发现 EV 本身就有助于实体瘤模型的耐药性。足以传递 ER 应激并激活受体基质中的未折叠蛋白反应 (UPR) 途径在体内，由于肿瘤微环境中的生理应激，AML 细胞表现出明显的 UPR。发现 UPR 途径的上调与表达和包装的增加相一致由于 UPR 和 BMP 先前都与促进癌症有关，因此将多种 BMP 类型移植到 EV 上。生存和耐药性，我们建议研究 EV 在将适应性变化传递给接受者方面的作用由于越来越多的证据表明 AML-EV，BM 细胞还形成了化学保护环境。重塑BM微环境、阻断EV生物发生已成为AML明显的治疗靶点。我们追求 EV 介导的未折叠蛋白反应和骨形态发生的传递蛋白质促进适应性变化，导致 AML 耐药，这种情况可以得到改善为了检验这一假设，在 AIM 1 中，我们将确定 EV 介导的贡献。 ER应激的传递促进受体基质细胞和AML细胞的化学保护性变化，以及确定抑制外泌体释放是否可以防止这些影响在目标 2 中，我们将确定 EV 是如何相关的。 BMP 失调基质细胞，并检查阻断 EV 释放和 BMP 受体信号传导对我们的长期目标是回答有关 AML 细胞如何逃避的长期问题。化疗并开发新的治疗策略以减少 AML 患者的耐药性。