Research Specialist Support for Defining the Roles of Bone Marrow Adipocytes and FABP4/5 Signaling in Multiple Myeloma

项目摘要 癌症的发展和最终的繁荣是由于肿瘤细胞本身的性质以及 肿瘤生长的微环境或‘土壤’。多发性骨髓瘤，一种血癌，由 突变的浆细胞，生长在骨髓的肥沃土壤中，导致骨骼崩溃。存在以下风险 骨髓瘤发生在老年人和体重指数高的人中更严重，这些人通常也 比年轻或苗条的人有更多的骨髓脂肪组织或脂肪。然而，这种关系 骨髓脂肪细胞(脂肪细胞)和骨髓瘤细胞之间的关系及其具体机制 骨髓脂肪细胞对骨髓瘤疾病进展的调节作用尚不清楚。因此，我们的目标是 寻找治疗多发性骨髓瘤的新途径，解锁新的 骨髓瘤细胞和骨髓脂肪细胞之间的相互作用特有的脆弱性，这可能 作为脂肪酸和亲骨髓瘤细胞因子的来源。我们的细胞培养研究表明骨髓 脂肪细胞诱导骨髓瘤细胞产生耐药性--这是骨髓瘤患者的常见问题。 我们已经发现，脂肪细胞与骨髓瘤细胞的串扰连接机制之一是通过蛋白质。 称为脂肪酸结合蛋白4和5(FABP4和FABP5)。我们将分析骨髓脂肪细胞如何 通过使用新的三维(3D)组织工程癌症模型来促进骨髓瘤 由骨髓脂肪细胞和骨髓瘤细胞在丝质支架上共同生长组成。通过不断增长的骨髓瘤 在这些3D迷你骨骼环境中，我们可以确定骨髓瘤细胞对 并发现针对这种相互作用的新方法。我们还将使用我们的新型鼠标模型来 通过增加或去除小鼠骨髓脂肪细胞研究骨髓脂肪细胞-骨髓瘤串扰 以及量化对肿瘤生长和耐药性的影响。我们将使用这些体外和体内模型来 具体测试FABP4和FABP5在肿瘤进展和耐药性中的作用，并努力实现我们的 长期目标是更好地了解推动多发性骨髓瘤生长的分子和机制 骨髓，以及癌症是如何为了自己的目的劫持这个利基的。这项提案支持这一努力 通过为研究专家提供支持以进一步开发、领导和执行实验 描述了询问细胞“土壤”的一个新部分(骨髓脂肪细胞)，在其中的肿瘤 细胞，或“种子”，在土地上生长。

Project Summary Cancer develops and ultimately flourishes due to both the nature of the tumor cells themselves as well as the microenvironment or ‘soil’ in which the tumor thrives. Multiple myeloma, a blood cancer that results from mutated plasma cells, grows in the rich soil of the bone marrow causing breakdown of the bone. The risk of developing myeloma is greater in older individuals and people with high body mass index who also typically have more bone marrow adipose tissue, or fat, than younger or leaner individuals. However, the relationship between bone marrow adipocytes (fat cells) and myeloma cells, as well as the specific mechanisms by which bone marrow adipocytes modulate myeloma disease progression are not well understood. Therefore, we aim to identify novel therapeutic avenues for the treatment of multiple myeloma patients by unlocking new vulnerabilities specific to the interactions between myeloma cells and bone marrow adipocytes, which can serve as a source of fatty acids and pro-myeloma cytokines. Our cell culture studies suggest bone marrow adipocytes induce drug resistance in myeloma cells- recapitulating a common problem for myeloma patients. We have found that one mechanism of cross-talk linking adipocytes with myeloma cells is through proteins called fatty acid-binding proteins 4 and 5 (FABP4 and FABP5). We will analyze how bone marrow adipocytes contribute to myeloma by using novel, three-dimensional (3D), tissue engineered cancer models which consist of bone marrow adipocytes and myeloma cells grown together on silk scaffolds. 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. We will also use our novel mouse models to study bone marrow adipocyte- myeloma crosstalk by increasing or removing bone marrow adipocytes in mice and quantifying effects on tumor growth and drug resistance. We will use these in vitro and in vivo models to specifically test the role of FABP4 and FABP5 in tumor progression and drug resistance, and work toward our long-term goal to better understand the molecules and mechanisms driving multiple myeloma growth in the bone marrow, and how cancer hijacks this niche for its own purposes. This proposal supports this endeavor by providing support for a Research Specialist to further develop, lead, and execute the experiments described which interrogate a novel part of the cellular “soil” (the bone marrow adipocyte), in which tumor cells, or “seeds” land and grow.