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

癌症的发展和扩散是由于肿瘤的性质和所处的微环境或“土壤” 肿瘤被嵌入了。多发性骨髓瘤是一种血癌，它是由积累在 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，不会造成 损伤或症状，然后更快和更具侵略性，导致骨骼退化和 抗药性克隆的发展。患骨髓瘤的风险在老年人和 体重指数高的人。这些患者通常也有更多的骨髓脂肪组织， 而不是更年轻或更苗条的个体。然而，骨髓脂肪细胞(脂肪细胞)调节的方式 疾病的发展还没有被很好地理解。因此，我们的目标是找到新的治疗途径来阻止多发性 通过靶向骨髓瘤细胞和骨髓脂肪细胞之间的相互作用进行骨髓瘤进展 为患者带来更好的治疗方法。由于骨髓脂肪具有潜在的炎症性质 组织及其作为脂肪酸和脂肪因子来源的能力，我们想要探索骨髓是如何 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可以诱导 骨髓瘤细胞通过脂肪酸结合蛋白4和5(FABP4和FABP4)产生耐药性 FABP5)。在这项提案的具体目标1中，我们将分析骨髓脂肪细胞如何对 骨髓瘤通过使用新的三维(3D)组织工程化癌症模型。相比之下，两个- 立体(2D)文化，3D文化更逼真地概括了人体内发生的事情。 组织工程模型由丝质支架、骨髓脂肪细胞和癌细胞制成。通过 在这些3D迷你骨骼环境中生长骨髓瘤细胞，我们可以确定骨髓瘤细胞在 对脂肪细胞的反应，并发现以这种相互作用为靶点的新方法。在我们提案的具体目标2中，我们 将用小鼠模型研究骨髓脂肪细胞和骨髓瘤的串扰。我们的小鼠模型 非常详细地概括了肿瘤是如何在患者体内生长的。我们将测试如何增加或移除骨髓 小鼠脂肪细胞影响肿瘤生长和耐药性，我们将专门测试FABP4的作用 和FABP5在这一过程中。我们将使用我们已经开发的这些体外和体内模型 并在我们的实验室进行了优化，以更好地了解癌症如何劫持骨髓利基以达到其自身目的。 我们的长期目标是了解骨多发性骨髓瘤生长的分子和机制。 骨髓。这一建议通过询问细胞“土壤”的一个新部分(骨髓)来补充这一点 脂肪细胞)，肿瘤细胞或“种子”在其中落地和生长。总而言之，我们的研究将确定反馈循环 在宿主和癌细胞之间，指出这种相互作用的中介，并提出范式转换的概念 指导抗骨髓瘤新疗法的开发。

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.