On September 3, 2025, researchers from the Princeton Branch of the Ludwig Institute for Cancer Research revealed crucial findings regarding the spread of breast cancer to the bones. This research highlights how specific adaptations in cancer cells contribute to the development of bone metastases, which are often resistant to treatment and lead to poor patient outcomes. The study identifies a mechanism behind the common complication of anemia in patients with bone metastases, shedding light on how these cancer cells thrive in an oxygen-poor environment.
Understanding the Mechanisms of Anemia in Bone Metastases
Breast cancer frequently metastasizes to the bone, forming tumors that disrupt normal bodily functions, including the production of blood cells. Anemia, characterized by a deficiency in the oxygen-carrying capacity of the blood, is one of the most prevalent complications associated with these metastases. Historically, the specific causes of this anemia remained unclear, but recent investigations led by Yibin Kang and Yujiao Han have provided significant insights.
In their study published in the journal Cell, Kang and Han explored the bone marrow niche where these tumors develop. They found that breast cancer cells employ two clever strategies to secure the metabolic support necessary for their survival and growth within the challenging microenvironment. These adaptations directly interfere with the function of specialized cells in the bone marrow responsible for producing red blood cells, thus causing anemia in patients.
“Targeting these metabolic transactions between cancer cells and specialized cells of the bone marrow microenvironment could lead to novel therapies that disrupt tumor growth while preserving bone marrow function and alleviating anemia,” Kang stated.
Strategies Employed by Cancer Cells
Metastasis poses a significant challenge for cancer cells. Only a select few within a tumor possess the necessary skills to migrate and establish new growths in distant organs. This process demands both survival during migration and the ability to adapt to the hostile environments of new tissues. The study highlights how cancer cells mimic local cell properties to manage the metabolic demands of their new surroundings. Additionally, they manipulate nearby noncancerous cells to obtain essential nutrients.
A key focus of the researchers was on iron availability, which is critical for the production of hemoglobin in red blood cells. They observed that a specialized type of immune cell known as the erythroblast island (EBI) macrophage is prevalent in the metastatic niche and clusters around cancer cells. In healthy bone marrow, these macrophages play a vital role in providing iron to erythroblasts, which are the precursors to red blood cells.
“We found that EBI-macrophages are hijacked by metastatic breast tumor cells to acquire iron, depriving erythroblasts of a mineral essential to the production of red blood cells,” Han explained. “Depleting these macrophages in mice impaired bone metastasis of breast cancer.”
The research also indicates that similar iron-managing macrophages are present in human bone metastases from other cancers, including lung and kidney tumors. This suggests that the hijacking of iron-recycling macrophages might be a widespread phenomenon among cancers that spread to the bone.
With a dedicated source of iron secured, breast cancer cells begin to mimic erythroblasts, expressing β-globin, a component of hemoglobin. This adaptation allows them to better survive in the low-oxygen conditions prevalent in bone marrow. The study shows a correlation between elevated β-globin expression in tumor cells and an increased risk of bone metastasis.
The dual adaptations observed have synergistic effects. By commandeering EBI-macrophages, cancer cells monopolize local iron resources, thereby disrupting the production of new red blood cells. This, in turn, allows the cancer cells to utilize the acquired iron to support their growth, further impairing erythroblast function.
“We’ve uncovered a novel axis of tumor-immune-metabolic crosstalk that promotes both metastatic progression and cancer-associated anemia,” Kang added. “Our work illustrates the remarkable plasticity of metastatic cells that grow in the bone and identifies a potential mechanism underlying the anemia caused by such metastases.”
This pioneering research was supported by several organizations, including the Ludwig Institute for Cancer Research, the American Cancer Society, the Charles H. Revson Foundation, the Brewster Foundation, the Breast Cancer Research Foundation, and the Susan G. Komen Foundation. Alongside his role at the Ludwig Institute, Yibin Kang serves as the Warner-Lambert/Parke-Davis Professor of Molecular Biology at Princeton University and is an Associate Director at the Rutgers Cancer Institute of New Jersey.
