Researchers at Baylor College of Medicine and collaborating institutions developed a method that reveals the cellular makeup of tissues that support metastatic cancer growth, which is the primary cause of death for most patients with solid tumors. The method not only revealed cellular features shared by metastatic niches of multiple cancer models but also uncovered an unexpected driver of immune suppression in bone metastasis. The study appeared in the journal Cell .
"As tumors progress, cancer cells leave the original site and spread or metastasize to other organs where they seed new tumors," said corresponding author Dr. Xiang Zhang , William T. Butler, M.D., Endowed Chair for Distinguished Faculty, professor of molecular and cellular biology and director of the Lester and Sue Smith Breast Center at Baylor. Zhang also is a member of Baylor's Dan L Duncan Comprehensive Cancer Center. "Our lab is interested in better understanding what cellular and molecular features support metastasis as these could guide the development of therapies to prevent, slow down or eliminate them. In the current study, we first developed a new method to identify the makeup of metastatic niches."
During metastasis, cancer cells interact constantly with other normal cells in the body, and these interactions affect cell behavior, fate and even response to therapies. "Our method allowed us to identify specific cells encountered by cancer cells during metastasis," said co-first author Fengshuo Liu , graduate student in the Cancer and Cell Biology Program working in the Zhang lab . "The method, called Sortase A–Based Microenvironment Niche Tagging (SAMENT), selectively labels normal cells that come into direct contact with cancer cells."
SAMENT revealed that pro-metastatic microenvironments of multiple cancer models in all the organs studied, including bone, lung, liver and brain, shared common features, including an abundance of immune cells called macrophages and shortage or absence of immune T cells, which typically help fight tumors.
"However, bone metastases stood out," said Liu. "We were surprised to find that macrophages surrounding cancer cells in bone metastases activated a protein called estrogen receptor alpha (ERα). This protein is best known for its role in hormone-responsive breast cancer but is much less studied in macrophages or other immune cells."
Macrophages with active ERα signaling were not detected in normal bone or in primary tumors in other tissues. ERα-active macrophages were also present in human bone metastasis samples from patients with breast, lung and kidney cancers – including male patients. This showed that this finding is not limited to one cancer type or to women.
The researchers also investigated how cancer cells turned macrophages, which would typically fight cancer, into their allies. Cancer cells deliver small molecules called fatty acids to macrophages, likely through tiny particles known as extracellular vesicles. These fatty acids activate a metabolic pathway in macrophages that turns on ERα signaling.
Once ERα is active, macrophages become immunosuppressive – instead of helping the immune system attack cancer, they form a barrier that physically and chemically blocks T cells from reaching tumor cells. ERα-active macrophages act as bodyguards for metastatic cancer in bone.
"To test whether ERα in macrophages can drive bone metastasis, we genetically removed the ERα gene specifically from macrophages in mice," Liu said. "As a result, cancer cells were far less able to colonize bone in multiple cancer models. Tumors grew more slowly, and metastases in other organs that often arise from bone tumors were also reduced. Importantly, removing ERα from macrophages did not disrupt normal bone health – bone structure and remodeling remained intact."
"When macrophage ERα was genetically removed or when mice were treated with fulvestrant, an FDA-approved cancer drug that degrades estrogen receptors, T cells were able to enter metastatic lesions in bone and kill tumor cells," Zhang said. "Our findings support conducting future human clinical trials to assess the value of estrogen-blocking therapies combined with other therapies to treat bone metastases across multiple cancer types, in both women and men."
For a complete list of contributors to this work, their affiliations and financial support for this study, see the publication.
