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.

项目总结/摘要 骨骼肌损失和无力是癌症恶病质的关键部分，并且与临床表现不佳相关。 结果和癌症患者的生活质量差。尽管以前在理解方面取得了进展， 癌症恶病质的机制，很少有人知道乳腺癌的存在如何影响骨骼 目前还没有针对癌症相关肌肉损失的早期检测方法或治疗， 恶病质拟议的项目将调查这一独特的方面肿瘤主机串扰从小说 癌症分泌的细胞外囊泡（EV）的前景，其在转移癌源性 最近已经认识到各种类型的正常细胞的信号。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。 我们将测试新的假设，即癌症分泌的EV的miRNA和蛋白质货物诱导肌肉 通过激活钙依赖性钙蛋白酶和泛素-蛋白酶体的蛋白质降解 系统在目标1中，我们将首先确定乳腺癌分泌的EV的选择性miRNA货物如何失调 在肌肉细胞中的钙转运，以激活钙蛋白酶并促进肌肉蛋白质分解。使用小鼠 模型，我们将评估这种机制在多大程度上有助于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以及这如何激活泛素-蛋白酶体系统 促进蛋白质降解。巨噬细胞和炎性细胞因子的作用将通过使用 小鼠模型。在目标2中，我们将评估靶向EV介导的免疫抑制剂的潜在疗法的有益作用。 对骨骼肌的作用机制实验性治疗方法将单独评估或在 组合在小鼠模型中保护肌肉免受所选EV的破坏性作用的功效 货物操纵装置治疗剂将在癌症相关的骨骼肌损失之前或之后施用。 检测，以评估其在预防和治疗环境中的表现。目标3：分析血液 乳腺癌患者的样本和计算机断层扫描图像，以评估 选择的EV货物分子和骨骼肌损失的参数之间的关系。拟定的研究将 为癌症对骨骼肌的远期影响提供了新的认识。它还将确立 用于预防或治疗癌症相关肌肉损失和恶病质的新治疗策略， 通过恢复肌肉功能改善癌症患者的生活质量，并间接提高抗癌 我们的长期目标是提供更好的癌症护理，并取得更好的结果， 患者