All ETDs from UAB

Advisory Committee Chair

Yang Yang

Advisory Committee Members

Krista Casazza

Amjad Javed

Deniz Peker

Rosa Serra

Majd Zayzafoon

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Multiple myeloma (MM) is a hematological malignancy of plasma cells that is intrinsically tied to the bone marrow (BM). Many cells in the BM microenvironment have been studied in MM, yet there is still much progress to be made. Recent work has revealed two new potential cellular targets in MM: adipocytes and osteocytes. Both are endocrine cells and secrete many molecules that regulate other cells proximally and systemically. Our lab previously showed that MM cells shift osteoblast precursor cells towards adipogenesis through soluble molecules alone. Recent findings also revealed that osteocyte apoptosis is enhanced in MM patients compared to healthy individuals. Therefore, we hypothesized that these changes are not only consequences of MM, but an increase in adipocytes and osteocyte apoptosis can feed back to MM cells to promote subsequent metastasis and progression. Herein, we first demonstrate that MM patients have a shift towards adipogenesis, including increased pre-adipocytes and larger mature adipocytes. We show that both pre-adipocytes and mature adipocytes secrete soluble molecules, such as SDF-1α and MCP-1, that recruit MM cells. In addition, pre-adipocytes and mature adipocytes had different but complimentary effects on MM cells. After co-culture with pre-adipocytes MM cells showed enhanced migration in vitro and greater metastasis and tumor growth in vivo, whereas culture in mature adipocyte CM promoted MM growth. We also demonstrate that MM cells induce osteocyte apoptosis in distant bone before metastasis. We developed a syngenic model of MM with selective osteocyte apoptosis to test the effect of osteocyte apoptosis on MM progression. Ultimately, osteocyte apoptosis resulted in increased MM tumor growth in bone and bone to bone metastasis. This is likely due to regulation of the BM microenvironment, as we found increased immune suppressive cells, decreased antigen presenting cells, and alterations in adipocytes, osteoblasts, osteoclasts, and vasculature after osteocyte apoptosis. Intriguingly, mice with osteocyte apoptosis had a blunted immune response, indicating a link between osteocytes and the immune system. Finally, we show that osteocytes have direct anti-MM effects that can be somewhat abrogated by apoptotic osteocytes. Combined, our data indicate that both adipocytes and osteocytes are important members of the BM microenvironment and targeting these cells has implications for MM cell progression and the tumor microenvironment as a whole.

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