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

研究专家支持定义骨髓脂肪细胞和 FABP4/5 信号转导在多发性骨髓瘤中的作用

• 批准号: 10683321
• 负责人: Heather F Campbell
• 金额: $ 9.96万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-12 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683321
• 关键词: 3-Dimensional; Adipocytes; Adipose tissue; Automobile Driving; Bone Marrow; Cancer Model; Cell Culture Techniques; Cells; Disease Progression; Drug resistance; Environment; FABP4 gene; FABP5 gene; Fatty Acids; Fatty acid glycerol esters; Goals; Growth; Hematopoietic Neoplasms; In Vitro; Individual; Intervention; Lead; Link; Malignant Neoplasms; Multiple Myeloma; Mus; Mutate; Nature; Patients; Persons; Plasma Cells; Proteins; Quality of life; Research; Risk; Role; Signal Transduction; Silk; Soil; Source; Specialist; Testing; Tissue Engineering; Work; bone; cancer drug resistance; cytokine; experimental study; fatty acid-binding proteins; high body mass index; improved; in vivo Model; mouse model; neoplastic cell; novel; novel therapeutics; response; scaffold; tumor; tumor growth; tumor progression

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.

项目总结