Defining the Roles of Bone Marrow Adipocytes and FABP4/5 Signaling in Multiple Myeloma Drug Resistance

定义骨髓脂肪细胞和 FABP4/5 信号在多发性骨髓瘤耐药中的作用

• 批准号: 10165671
• 负责人: Michaela R Reagan
• 金额: $ 39.35万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 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/10165671
• 关键词: 3-Dimensional; Address; Adipocytes; Adipose tissue; Adult; Affect; Aging; Automobile Driving; B-Cell Neoplasm; Biological; Bone Development; Bone Diseases; Bone Marrow; Bone Marrow Cells; Cancer Model; Cell Culture Techniques; Cell Proliferation; Cell Survival; Cells; Clinical; Coculture Techniques; Data; Development; Dimensions; Disease Progression; Disease Resistance; Drug resistance; Energy Metabolism; Energy-Generating Resources; Environment; Exhibits; Exposure to; FABP4 gene; FABP5 gene; Fatty Acids; Fatty acid glycerol esters; Feedback; Feeds; Gene Expression; Gene Proteins; Generations; Genetic; Genetic Models; Goals; Growth; Hematopoietic Neoplasms; High Fat Diet; Homing; Human; Human body; IL6 gene; In Vitro; Individual; Inflammatory; Intervention; Laboratories; Lead; Lipids; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Mediator of activation protein; Messenger RNA; Modeling; Multiple Myeloma; Mus; Mutation; Nature; Nonesterified Fatty Acids; Obesity; PI3K/AKT; PPARG gene; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasma Cells; Process; Proteins; Quality of life; Research; Resources; Risk; Risk Factors; Role; Seeds; Signal Transduction; Silk; Soil; Source; Sum; Symptoms; Testing; Therapeutic; Thinness; Tissue Engineering; adipokines; autocrine; base; bone; cancer cell; cancer drug resistance; dietary; experience; fatty acid-binding proteins; high body mass index; improved; in vivo; in vivo Model; instrument; lipid metabolism; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; paracrine; physiologic model; prevent; protein expression; resistance mechanism; response; scaffold; survival outcome; targeted treatment; therapy resistant; three dimensional cell culture; tumor; tumor growth; tumor microenvironment; two-dimensional; uptake

Cancer develops and spreads because of the nature of the tumor and the microenvironment or `soil' in which the tumor is embedded. Multiple myeloma is a blood cancer that results from mutations that accumulate in a plasma cell. Multiple myeloma cells grow in the rich soil of the bone marrow, first very slowly, causing no damage or symptoms, and then more quickly and aggressively, causing degradation of the bone and development of drug resistant clones. The risk of developing myeloma is greater in older individuals and people with high body mass index. These patients also typically have more bone marrow adipose tissue, or fat, than younger or leaner individuals. However, the ways in which bone marrow adipocytes (fat cells) modulate disease progression are not well understood. Thus, we aim to identify new therapeutic avenues to halt multiple myeloma progression by targeting the interactions between myeloma cells and bone marrow adipocytes to lead to better therapeutics for patients. Due to the potentially inflammatory nature of bone marrow adipose tissue, and its ability to act as a source of fatty acids and adipokines, we wanted to explore how bone marrow adipose tissue affects myeloma tumor cells. Our cell culture studies suggest bone marrow adipocytes induce drug resistance in myeloma cells through proteins called fatty acid-binding proteins 4 and 5 (FABP4 and FABP5). In Specific Aim 1 of this proposal, we will analyze how bone marrow adipocytes contribute to myeloma by using novel, three-dimensional (3D), tissue engineered cancer models. Compared to two- dimensional (2D) cultures, 3D cultures much more realistically recapitulate what happens in the human body. The tissue engineered models are made from silk scaffolds, bone marrow adipocytes, and cancer cells. By growing myeloma cells in these 3D mini-bone environments, we can determine how myeloma cells change in response to adipocytes and discover new ways to target this interaction. In Specific Aim 2 of our proposal, we will use mouse models to study bone marrow adipocyte and myeloma crosstalk. Our mouse models recapitulate very closely how tumors grow in patients. We will test how increasing or removing bone marrow adipocytes in mice affects tumor growth and drug resistance, and we will test specifically the role of FABP4 and FABP5 in this process. We will use these in vitro and in vivo models, which we have already developed and optimized in our lab, to better understand how cancer hijacks the bone marrow niche for its own purposes. Our long-term goal is to understand molecules and mechanisms driving multiple myeloma growth in the bone marrow. This proposal feeds into that by interrogating a novel part of the cellular “soil” (the bone marrow adipocyte), in which tumor cells, or “seeds” land and grow. In sum, our research will identify feedback loops between host and cancer cells, indicate mediators of this interaction, and propose paradigm-shifting concepts to guide the development of new anti-myeloma therapies.

癌症的发展和扩散是由于肿瘤的性质和微环境或其中的“土壤”。 肿瘤已经嵌入多发性骨髓瘤是一种血液癌症，其起因于细胞中积累的突变。 浆细胞多发性骨髓瘤细胞在骨髓的肥沃土壤中生长，首先非常缓慢，导致没有细胞生长。 损伤或症状，然后更快，更积极地，造成骨退化， 抗药性克隆的发展。老年人患骨髓瘤的风险更大， 体重指数高的人这些患者通常也有更多的骨髓脂肪组织，或脂肪， 更年轻或更瘦的人。然而，骨髓脂肪细胞调节 疾病的进展还不清楚。因此，我们的目标是确定新的治疗途径，以阻止多个 通过靶向骨髓瘤细胞和骨髓脂肪细胞之间的相互作用， 为病人带来更好的治疗方法。由于骨髓脂肪的潜在炎症性质， 组织，以及它作为脂肪酸和脂肪因子来源的能力，我们想探索骨髓 脂肪组织影响骨髓瘤肿瘤细胞。我们的细胞培养研究表明骨髓脂肪细胞诱导 通过称为脂肪酸结合蛋白4和5（FABP 4和5）的蛋白质在骨髓瘤细胞中产生耐药性。 FABP5）。在本提案的具体目标1中，我们将分析骨髓脂肪细胞如何有助于 通过使用新型的三维（3D）组织工程癌症模型来治疗骨髓瘤。相比之下，两个- 三维（2D）文化，3D文化更现实地概括了人体中发生的事情。 组织工程模型由蚕丝支架、骨髓脂肪细胞和癌细胞制成。通过 通过在这些3D迷你骨环境中培养骨髓瘤细胞，我们可以确定骨髓瘤细胞在 并发现针对这种相互作用的新方法。在我们提案的具体目标2中，我们 将使用小鼠模型来研究骨髓脂肪细胞和骨髓瘤串扰。我们的小鼠模型 非常接近地概括了肿瘤是如何在病人体内生长的。我们将测试增加或移除骨髓 小鼠脂肪细胞影响肿瘤生长和耐药性，我们将专门测试FABP 4的作用。 FABP 5在这个过程中我们将使用这些体外和体内模型，我们已经开发了 并在我们的实验室中进行了优化，以更好地了解癌症如何劫持骨髓生态位以达到其自身目的。 我们的长期目标是了解驱动多发性骨髓瘤在骨骼中生长的分子和机制 骨髓这个建议通过询问细胞“土壤”（骨髓）的一个新部分来补充 脂肪细胞），其中肿瘤细胞或“种子”着陆并生长。总之，我们的研究将确定反馈回路 宿主和癌细胞之间的相互作用，表明这种相互作用的介质，并提出范式转变的概念， 以指导新的抗骨髓瘤疗法的开发。