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

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.

Grant Number: 5R50CA265331-04
NIH Institute/Center: NIH
Principal Investigator: Heather Campbell