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Principal Investigator: Michaela R. Reagan
Organization: MAINEHEALTH
Fiscal Year: 2024
Award: $373,778
Funding agency: National Cancer Institute
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.
Terms: <1-Phosphatidylinositol 3-Kinase><2-dimensional><21+ years old><3-D><3-Dimensional><3D><A-FABP><Address><Adipocytes><Adipose Cell><Adipose tissue><Adult><Adult Human><Affect><Aging><Autocrine Systems><Automobile Driving><B cell tumor><B-Cell Differentiation Factor Gene><B-Cell Lymphocytic Neoplasm><B-Cell Neoplasm><B-Cell Stimulatory Factor 2 Gene><B-lineage tumor><BSF-2 Gene><BSF2 Gene><Beta-2 Gene Interferon><Biological><Blood Plasma Cell><Bone Diseases><Bone Marrow><Bone Marrow Blood-Deriving Cell><Bone Marrow Blood-Forming Cell><Bone Marrow Cells><Bone Marrow Reticuloendothelial System><Cancer Model><CancerModel><Cancers><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Proliferation><Clinical><Co-culture><Cocultivation><Coculture><Coculture Techniques><Compensation><Data><Development><Dimensions><Disease Progression><Disease Resistance><Drug Therapy><Drug resistance><E-FABP><Energy Expenditure><Energy Metabolism><Energy-Generating Resources><Environment><Exhibits><Exposure to><Extracellular Signal-Regulated Kinase Gene><FABP4><FABP4 gene><FABP5><FABP5 gene><Fat Cells><Fats><Fatty Acid Binding Protein 4, Adipocyte><Fatty Acids><Fatty Tissue><Fatty acid glycerol esters><Feedback><Feeds><Fracture><Free Fatty Acids><Gene Expression><Generalized Growth><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Models><Genetic defect><Goals><Growth><HSF Gene><HUMPPARG><Hematopoietic Cell Tumor><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Hepatocyte Stimulatory Factor Gene><High Fat Diet><Homing><Human><Human Figure><Human body><Hybridoma Growth Factor Gene><IFNB2 Gene><IL-6 Gene><IL6><IL6 gene><In Vitro><Individual><Inflammatory><Interleukin 6 (Interferon, Beta 2) Gene><Interleukin-6 Gene><Intervention><Intervention Strategies><Intracellular Communication and Signaling><KFABP><Lab Findings><Laboratory Finding><Lipids><Lipocytes><MAP Kinase Gene><MAPK><Malignant><Malignant - descriptor><Malignant Cell><Malignant Hematopoietic Neoplasm><Malignant Neoplasms><Malignant Tumor><Mature Lipocyte><Mature fat cell><Mediator><Messenger RNA><Mice><Mice Mammals><Mitogen-Activated Protein Kinase Gene><Modeling><Modern Man><Multiple Myeloma><Murine><Mus><Mutation><NR1C3><Nature><Nonesterified Fatty Acids><Obesity><Older Population><Osteolysis><Osteoporosis><PA-FABP><PI-3 Kinase><PI-3K/AKT><PI3-Kinase><PI3CG><PI3K/AKT><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PPARG><PPARG gene><PPARG1><PPARG2><Pathway interactions><Patients><Pattern><Pharmacotherapy><Phenotype><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Plasma Cells><Plasma-Cell Myeloma><Plasmacytes><Process><Proliferating><Proteins><PtdIns 3-Kinase><QOL><Quality of life><Research><Research Resources><Resources><Risk><Risk Factors><Role><Signal Induction><Signal Transduction><Signal Transduction Systems><Signaling><Silk><Soil><Source><Symptoms><Testing><Therapeutic><Tissue Engineering><Tissue Growth><Tissue Model><Tumor Cell><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><adipocytokines><adipokines><adipose><adiposity><adulthood><autocrine><bioengineered tissue><biologic><biological signal transduction><blood cancer><bone><bone disorder><bone fracture><cancer cell><cancer drug resistance><cancer of blood><cancer of the blood><cell culture><cell cultures><corpulence><develop drug resistance><developmental><dietary><driving><drug development><drug resistance development><drug resistant><drug treatment><energy source><engineered tissue><experience><fat metabolism><fatty acid-binding proteins><genome mutation><high BMI><high body mass index><improved><in vivo><in vivo Model><instrument><interventional strategy><lipid metabolism><mRNA><malignancy><mouse model><murine model><myeloma><myelomatosis><neoplasm/cancer><neoplastic cell><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><older groups><older individuals><older person><ontogeny><paracrine><pathway><pharmacologic><physiologic model><plasmocyte><prevent><preventing><protein expression><resistance mechanism><resistance to Drug><resistance to cancer drugs><resistance to disease><resistance to therapy><resistant disease><resistant mechanism><resistant to Drug><resistant to cancer drugs><resistant to disease><resistant to therapy><response><scaffold><scaffolding><social role><survival outcome><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapy resistant><three dimensional><treatment resistance><tumor><tumor growth><two-dimensional><uptake><white adipose tissue><yellow adipose tissue>