Cancer specialists have long known that anemia, caused by a lack of healthy red blood cells, often arises when cancer metastasizes to the bone, but it's been unclear why. Now, a research team led by Princeton University researchers Yibin Kang and Yujiao Han has uncovered exactly how this happens in metastatic breast cancer, and it involves a type of cellular hijacking. The research aims to help slow down bone metastasis – one of cancer's deadliest forms.
In a study forthcoming in the journal Cell on September 3, Kang and Han reveal that cancer cells effectively commandeer a specialized cell that normally recycles iron in the bone, known as an erythroblast island (EBI) macrophage. This both deprives red blood cells of necessary iron and helps the tumor continue to grow in the bone. Understanding metastatic cancer – or cancer that grows and spreads in other parts of the body beyond the original tumor site – is critically important. It is one of the deadliest forms of cancer and there is no cure. Of patients who die from breast and prostate cancer, 70% have bone metastasis.
"The hope is to slow down or treat bone metastasis and, at the same time, alleviate the complications of anemia," said Han, the study's lead author and an associate research scholar in the Department of Molecular Biology at Princeton.
Understanding the soil where cancer grows
Kang explained that the discovery represents a new research direction for his lab — one that shifts attention from the "seeds" of cancer to the "soil" in which it grows within a metastatic organ site. This idea, known as the "seed and soil hypothesis," was first proposed more than a century ago by British surgeon Stephen Paget. For much of the past two decades, Kang, who is a Warner-Lambert/Parke-Davis Professor of Molecular Biology at Princeton, and many others in the cancer biology field have focused primarily on the tumor cells themselves (the 'seeds') and how they adapt to spread and grow in bone. But to truly understand metastasis, he said, it is just as important to study the soil—the surrounding environment that nurtures or restrains the cancer.
Until recently, however, the "soil" of the bone marrow remained largely uncharted. "It has been a big black hole," Kang said, who is also a founding member of the Princeton Branch of the Ludwig Institute for Cancer Research. "We did not have a comprehensive understanding of what the soil is made of."
That has begun to change with the advent of advanced cell-labeling and single-cell sequencing technologies, which allowed Kang's team to map the bone marrow in unprecedented detail. Kang, Han and colleagues were able to identify and visualize clusters of specialized macrophages gathering around the tumor—cells that should have been supporting red blood cell production but, instead, were diverted to serve the cancer.
How cancer cells trick healthy ones
Under healthy conditions, these macrophages act as "nurse cells," feeding iron to developing red blood cells so they can mature and carry oxygen. But in the presence of bone metastases, the tumor lures these macrophages to its side using signaling molecules, then diverts their iron away from red blood cells. In addition, the disruption goes beyond iron loss alone. Kang and Han found that the tumor-exploited macrophages also fail to support the final maturation step of red blood cells—the expulsion of their nuclei—further stalling red blood cell development and worsening anemia. This starves the bone marrow of the iron needed for healthy red blood cell production and locks red blood cells in their immature state, leaving patients anemic.
At the same time, the cancer cells put the stolen iron to their own use. They adapt by mimicking red blood cells themselves. Under the guidance of a blood-cell transcription factor called GATA1, tumor cells begin producing hemoglobin, the same oxygen-transporting protein that fills red blood cells. This "red blood cell mimicry" allows the tumor to thrive in the bone's oxygen-poor environment, protecting the cancer cells from stress and helping them survive. In short, the tumor creates a vicious cycle: it co-opts the bone's iron-recycling system to feed itself, while simultaneously sabotaging the body's ability to make new red blood cells.
'It's essentially a wolf disguising itself as a sheep by eating similar food to what sheep eat, and that helps them survive better in the environment,' said Kang, who is also an associate director of Rutgers Cancer Institute of New Jersey.
Although the current study focused on metastatic breast cancer, the findings have been extended to other major cancer types and carry broad implications. By revealing how tumors manipulate their surroundings, the work opens new avenues for therapies designed not only to slow or stop bone metastasis but also to alleviate the debilitating anemia that so often accompanies it.
Full authors list: Yujiao Han,1, 2 Hirak Sarkar,2,3 Zhan Xu,4,5,6 Sereno Lopez-Darwin,7 Yong Wei,1, 2 Xiang Hang,1, 2 Fengshuo Liu,4,5,6,8 Kimberley Tran,1 Wei Wang,7 Jennifer M. Miller,7 Christina J. DeCoste,1 Dylan Blohm,1 Robert L. Satcher,9 Xiang H.-F. Zhang,4,5,6,10 Yibin Kang1,2,11,*
1Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
2Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ 08544, USA
3Department of Computer Science, Princeton University, Princeton, NJ 08544, USA
4Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza,
Houston, TX 77030, USA
5Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza,
Houston, TX 77030, USA
6Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor
Plaza, Houston, TX 77030, USA
7Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ
08544, USA
8Graduate Program in Cancer and Cell Biology, Baylor College of Medicine, One Baylor
Plaza, Houston, TX 77030, USA
9Department of Orthopedic Oncology, University of Texas, MD Anderson Cancer
Center, Houston, TX 77030, USA
10McNair Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX
77030, USA
11Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey,
New Brunswick, NJ 08903, USA
