Mechanistic study of skeletal muscle proteolysis induced by breast cancer-secreted extracellular vesicles

乳腺癌分泌的细胞外囊泡诱导骨骼肌蛋白水解的机制研究

• 批准号: 10704327
• 负责人: Simon Schenk
• 金额: $ 25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704327
• 关键词: Adoptive Transfer; Affect; Antisense Oligonucleotides; Area; Binding; Blood; Blood specimen; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Cachexia; Calcium; Calpain; Cancer Patient; Clinical; Collaborations; Data; Distant; Early Diagnosis; Encapsulated; Enzymes; Event; Functional disorder; Goals; Immunocompetent; Immunocompromised Host; Impairment; Individual; Inflammation; Inflammatory; Injections; Interleukin-6; Investigational Therapies; Knowledge; Linear Regressions; Macrophage Activation; Malignant Neoplasms; Mediating; MicroRNAs; Modeling; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Proteins; Muscle Weakness; Muscle function; Muscular Atrophy; Neoplasm Metastasis; Normal Cell; O-GlcNAc transferase; Outcome; Pathway interactions; Patients; Peptide Hydrolases; Performance; Pharmacology; Phosphorylation; Prevention; Preventive; Production; Proteins; Proteolysis; Psoas Muscles; Quality of life; Research; Research Personnel; Role; STAT3 gene; Sarcoplasmic Reticulum; Scanning; Signal Transduction; Skeletal Muscle; System; TLR2 gene; TNF gene; Testing; Therapeutic; Thick; Third lumbar vertebra; Time; Travel; Ubiquitin; Ubiquitination; Woman; X-Ray Computed Tomography; anticancer treatment; blood-based biomarker; breast imaging; cancer cachexia; cancer care; cancer cell; clinical translation; cytokine; detection method; extracellular vesicles; improved; inhibitor; innovation; macrophage; malignant breast neoplasm; malignant muscle neoplasm; mortality risk; mouse model; multicatalytic endopeptidase complex; muscle form; muscle physiology; mutant; novel; novel therapeutic intervention; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; pre-clinical; prevent; protein degradation; response; skeletal muscle wasting; therapeutic RNA; therapeutic target; treatment response; tumor; tumor growth; tumor microenvironment; tumor xenograft; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT Skeletal muscle loss and weakness are a key part of cancer cachexia and are associated with poor clinical outcomes and a poor quality of life in cancer patients. Despite previous advances in understanding the mechanisms of cancer cachexia, little is known about how the presence of breast cancer influences skeletal muscle, and no early detection method or therapy currently exists for cancer-associated muscle loss and cachexia. The proposed project will investigate this unique aspect of tumor–host crosstalk from the novel perspective of cancer-secreted extracellular vesicles (EVs), whose function in transferring cancer-derived signals to various types of normal cells has been recently recognized. The goal of this study is to identify the mechanisms by which breast cancer-secreted EVs dysregulate skeletal muscle mass and function. We will test the novel hypothesis that miRNA and protein cargo of cancer-secreted EVs induce muscle protein degradation by activating the calcium-dependent calpain proteases and the ubiquitin-proteasome system. In Aim 1, we will first determine how selected miRNA cargo of breast cancer-secreted EVs dysregulate calcium transport in muscle cells to activate calpains and promote muscle protein breakdown. Using mouse models, we will evaluate to what extent this mechanism contributes to cancer-associated muscle mass loss and dysfunction. Next, we will identify the mechanism through which breast cancer-secreted EVs stimulate macrophages to induce skeletal muscle inflammation and how this activates the ubiquitin-proteasome system to promote protein degradation. The role of macrophages and inflammatory cytokines will be determined using mouse models. In Aim 2, we will assess the beneficial effects of potential therapeutics targeting EV-mediated mechanisms on skeletal muscle. Experimental therapeutic approaches will be assessed individually or in combination in mouse models for the efficacy in protecting muscle from the devastating effect of selected EV cargo effectors. The therapeutics will be administered before or after cancer-associated skeletal muscle loss is detected, to assess their performance in the prevention and treatment settings. In Aim 3, we will analyze blood samples and computed tomography scan images from breast cancer patients, to assess the associations between selected EV cargo molecules and parameters of skeletal muscle loss. The proposed study will provide a new understanding of the distant effects of cancer on skeletal muscle. It will also establish rationales for novel therapeutic strategies to prevent or treat cancer-associated muscle loss and cachexia, which would improve the quality of life in cancer patients by restoring muscle function and indirectly improve anticancer treatment response towards our long-term objective to deliver better cancer care and achieve better results for patients.

项目概要/摘要 骨骼肌损失和无力是癌症恶病质的一个关键部分，并且与不良的临床表现相关。 癌症患者的结果和生活质量较差。尽管之前在理解方面取得了进展 癌症恶病质的机制，人们对乳腺癌的存在如何影响骨骼知之甚少 肌肉，目前还没有针对癌症相关肌肉损失和肌肉损失的早期检测方法或治疗方法 恶病质。拟议的项目将研究小说中肿瘤-宿主串扰的这一独特方面 癌症分泌的细胞外囊泡（EV）的观点，其在转移癌症来源的功能 最近已认识到向各种类型的正常细胞发出的信号。这项研究的目的是确定 乳腺癌分泌的 EV 失调骨骼肌质量和功能的机制。 我们将测试癌症分泌的 EV 的 miRNA 和蛋白质货物诱导肌肉的新假设 通过激活钙依赖性钙蛋白酶和泛素蛋白酶体来降解蛋白质 系统。在目标 1 中，我们将首先确定乳腺癌分泌的 EV 中选定的 miRNA 货物如何失调 肌肉细胞中的钙转运激活钙蛋白酶并促进肌肉蛋白质分解。使用鼠标 模型中，我们将评估这种机制在多大程度上导致癌症相关的肌肉质量损失 和功能障碍。接下来，我们将确定乳腺癌分泌的 EV 刺激的机制 巨噬细胞诱导骨骼肌炎症及其如何激活泛素蛋白酶体系统 以促进蛋白质降解。巨噬细胞和炎症细胞因子的作用将通过以下方法确定 鼠标模型。在目标 2 中，我们将评估针对 EV 介导的潜在疗法的有益效果 骨骼肌的机制。实验性治疗方法将单独或分批评估 小鼠模型中的组合可有效保护肌肉免受选定 EV 的破坏性影响 货物效应器。治疗将在癌症相关骨骼肌丧失之前或之后进行 检测，以评估他们在预防和治疗环境中的表现。在目标 3 中，我们将分析血液 来自乳腺癌患者的样本和计算机断层扫描图像，以评估相关性 选定的 EV 货物分子和骨骼肌损失参数之间的关系。拟议的研究将 提供了对癌症对骨骼肌的远距离影响的新认识。还将确定理由 寻找预防或治疗癌症相关肌肉损失和恶病质的新治疗策略，这将 通过恢复肌肉功能改善癌症患者的生活质量，间接提高抗癌能力 治疗反应以实现我们的长期目标，即提供更好的癌症护理并为患者取得更好的结果 患者。