Defining extracellular vesicle-mediated drug resistance in AML

定义 AML 中细胞外囊泡介导的耐药性

• 批准号: 10208834
• 负责人: John Thomas Butler
• 金额: $ 4.62万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2022-06-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208834
• 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; Chemoresistance; 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 cell expansion; therapeutic target; tool; trafficking; transmission process; tumor initiation; tumor microenvironment; tumor progression; uptake; vesicular release

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.

项目摘要 急性髓性白血病（AML）是一种侵袭性、遗传异质性癌症， 儿童和成人--其起因于骨髓（BM）中的异常髓样细胞。虽然许多患者 在诱导化疗后达到缓解，由于复发，5年生存率仍然只有25%， 对抗癌药物的抵抗力增强。AML重塑BM微环境，部分通过释放 膜结合的细胞外囊泡（EV），使受体细胞失调。我们发现电动汽车 内质网应激基质细胞，导致细胞类型特异性的表型变化，改变细胞的功能。 BM的细胞组成。有趣的是，这些EV也被发现含有骨形态发生蛋白 骨形态发生蛋白（BMP）-与耐药性和癌症进展有关的强效生长因子。目前所知甚少 关于EV介导的ER应激和BMPs的传递如何有助于形成化学保护生态位。 多项研究表明，ER应激可以在肿瘤微环境中的细胞之间传递， 导致实体瘤模型中的耐药性。在AML的背景下，我们发现电动汽车本身 足以传递ER应激并激活受体间质中的未折叠蛋白反应（UPR）途径 细胞在体内，由于肿瘤微环境中的生理应激，AML细胞表现出显著的UPR。我们有 发现UPR途径的上调与表达和包装的增加相一致， 多个BMP类型到EV上。由于UPR和BMPs先前都与促进癌症有关， 生存和耐药性，我们建议研究EV在将适应性变化传递给受体中的作用 BM细胞形成化学保护环境。此外，由于越来越多的证据表明AML-EV 重塑BM微环境，阻断EV生物合成已成为AML的明显治疗靶点。 我们假设EV介导的未折叠蛋白反应和骨形态发生的传递 蛋白质促进有助于AML耐药性的适应性变化，这可以改善 通过抑制电动汽车的释放。为了验证这一假设，在AIM 1中，我们将确定EV介导的 ER-应激的传递促进受体基质细胞和AML细胞中的化学保护性变化，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，我们将确定与EV相关的 BMPs失调基质细胞，并检查阻断EV释放和BMPs受体信号传导对基质细胞的影响。 AML进展。我们的长期目标是回答长期存在的关于AML细胞如何逃避 化疗和开发新的治疗策略，以减少AML患者的耐药性。