Subpopulations of Osteoblasts Are Present in the Bone-Tumor Niche During Bone Metastatic Breast Cancer
Abstract
Breast cancer is the most common cancer in American women and the second most common cause of cancer death. Metastatic breast cancer is responsible for the deaths of over 41,000 American women and men every year, and over 500,000 annual deaths worldwide. Bone is a common site of metastasis, and patients with bone metastasis report the worst quality of life of all sites of metastasis. In an adult, under normal conditions, bone is remodeled by bone-resorbing osteoclasts and bone-depositing osteoblasts, with no net gain or loss. When metastatic breast cancer cells invade the bone, this balance is disrupted. It is well established that there is substantial crosstalk between osteoblasts, osteoclasts, and breast cancer cells that invade bone, especially during advanced disease. In fact, our lab previously identified osteoblasts as key mediators of metastatic breast cancer cell colonization in bone (Bussard, et al. J Cell Biochem. 111: 2010; Bussard, et al. Clin Exp Mets. 27: 2010.). Interestingly, however, our most recent work led to the discovery of a subset of osteoblasts that slow down breast cancer cell growth in bone during early-stage metastasis (Kolb, et al. Breast Cancer Res. 21: 2019), suggesting that osteoblasts have tumor-inhibitory properties and may, in part, regulate breast cancer metastatic progression in bone. More excitingly, we have new data to suggest that this subset of osteoblasts also suppress the formation of bone-resorbing osteoclasts and may consequently reduce bone destruction associated with tumor progression. Therefore, we will investigate a new and previously unappreciated tumor-inhibitory role of osteoblasts during breast cancer progression in bone. For this proposal, we will address the BCRP’s overarching challenge to identify what drives breast cancer cell growth; determine how to stop it. We propose to study the role of the osteoblasts in early stages of breast cancer progression and to determine how osteoblasts can be engaged to exert their tumor-inhibitory effect. We have preliminary data showing that there are two distinct subsets of osteoblasts in the bone-tumor niche: one group, the “educated” osteoblasts, which have engaged in crosstalk with metastatic breast cancer cells, and a second, “uneducated” group, which has not. We have shown in cell culture that direct contact and exposure to factors produced by these “educated” osteoblasts (EOs) result in a decreased growth of both ER+ and triple-negative metastatic breast cancer cells. In mice injected with breast cancer cells plus EOs, tumor that formed grew slower and were significantly smaller compared to mice injected with breast cancer cells plus “uneducated” osteoblasts. And, our new data demonstrates that EOs suppress new formation of bone-resorbing osteoclasts and may reduce the bone destruction associated with metastatic progression in bone. Our laboratory is the first to describe these interactions. Thus, these results suggest EOs have tumor-inhibitory properties. Hypothesis: “Educated” osteoblasts are a unique subpopulation of osteoblasts that regulate breast cancer progression to metastasis via suppression of (1) breast cancer growth and (2) bone resorption. Aim 1: Define molecular mechanisms EOs use to suppress BC proliferation. Aim 2: Define factors that are unique to the EO cell subpopulation. Aim 3: Elucidate how EOs suppress osteoclast formation and reduce bone resorption. Impact: Better understanding of the role of osteoblasts in bone metastatic breast cancer and the way in which EOs exert their anti-tumor effects will pave the way for future therapies that may not only allow prevention of breast cancer progression and bone destruction, but may also provide a pathway for re-engaging osteoblasts to resume their bone-building function, thus alleviating the pain associated with bone metastatic breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110001
Entities
People
- Karen M Bussard
Organizations
- Thomas Jefferson University
- United States Army