SEPTEMBER 3, 2025, NEW YORK - Breast cancers frequently spread to the bone, establishing tumors that are largely impervious to treatment and are associated with poor patient prognoses. A deficiency in the oxygen-carrying capacity of the blood, or anemia, is among the most common complications of these common metastases. Though such anemia was thought to stem from the tumor's disruption of bone marrow-the body's manufacturing hub for all blood cells, including its oxygen-bearing red blood cells-its precise underlying causes were a mystery.
No longer. In exploring the niche in bone marrow where such tumors take root, researchers led by Yibin Kang and Yujiao Han of the Princeton Branch of the Ludwig Institute for Cancer Research uncovered a pair of canny strategies breast cancer cells employ to access the metabolic support essential to their survival and proliferation in the oxygen-poor microenvironment of bone marrow. These adaptations, they report in the current issue of Cell, directly disrupt the function of specialized bone marrow cells that produce red blood cells, causing the anemia that accompanies bone metastasis.
"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, a frequently overlooked but debilitating complication for women living with metastatic breast cancer," said Kang.
Metastasis is a tall order for the average cancer cell. Only a select few in any given tumor evolve the full suite of skills and capabilities required to sally forth and take root in other organs. These venturesome cells must not only survive a dangerous migration, through inhospitable terrain, to distant sites but also adapt extensively to the unfamiliar and frequently hostile microenvironments of alien tissues to establish a tumor. The latter feat often entails mimicking some properties of local cells to better handle the metabolic demands of their new home. It also typically involves the manipulation of noncancerous cells in the vicinity to furnish, among other things, the nutrients essential to cancer cell proliferation.
Iron is a case in point. Though bone marrow has healthy reserves of this essential mineral, it is not readily available to invading cancer cells. So Han, Kang and colleagues took note when they discovered that a highly specialized type of iron-recycling immune cell-the erythroblast island (EBI) macrophage-was noticeably abundant in the metastatic niche and seemed to cluster around cancer cells.
In healthy bone marrow, EBI-macrophages serve as nurse cells, providing iron to erythroblasts, the precursors of red blood cells. Erythroblasts need the mineral to make functional hemoglobin molecules, which red blood cells use to capture oxygen for dissemination throughout the body.
"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," said Han. "Depleting these macrophages in mice impaired bone metastasis of breast cancer."
The researchers show that similar iron-handling macrophages are found in human bone metastases not only from breast cancer, but also from lung and kidney tumors. This suggests that the hijacking of iron-recycling macrophages might be a common phenomenon in cancers that metastasize to the bone.
The researchers also discovered that with a dedicated source of iron now available to them, the cancer cells begin to mimic erythroblasts, expressing a component of hemoglobin-β-globin-to better survive the hypoxic environment in the bone marrow. And, again, this mimicry was reflected in human tumors: elevated β-globin expression in tumor cells, they show, is associated with an increased risk of bone metastasis.
The two adaptations have synergistic effects. By coopting EBI-macrophages, cancer cells corner the local market for iron in bone marrow, disrupting the generation of new red blood cells. They then use that iron to support their own survival and proliferation, which further compromises erythroblast function.
"We've uncovered a novel axis of tumor-immune-metabolic crosstalk that promotes both metastatic progression and cancer-associated anemia," said Kang. "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. These findings can be exploited for the development of therapies that could improve both the survival and the quality of life of cancer patients."
This work was supported by 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.
Aside from his post as a Member of the Princeton Branch of the Ludwig Institute for Cancer Research, Yibin Kang is Warner-Lambert/Parke-Davis Professor of Molecular Biology at Princeton University and an Associate Director of Rutgers Cancer Institute of New Jersey.
