Researchers at Baylor College of Medicine developed a powerful new technique that maps the cellular environments enabling cancer to spread. Their findings point to an unexpected immune-suppressing mechanism in bone metastasis — and a potential treatment already on pharmacy shelves.
Scientists at Baylor College of Medicine and colleagues at collaborating institutions have developed a new method that maps the cellular landscape surrounding metastatic tumors, uncovering a surprising mechanism by which cancer cells turn the body’s own immune defenders against themselves — particularly in bone.
The research, published April 28 in the journal Cell, could reshape how doctors approach bone metastasis, a leading cause of death among patients with solid tumors like breast, lung and kidney cancer.
Why Metastasis Is So Deadly
When cancer spreads beyond its original site, survival odds drop dramatically. The cancer cells don’t travel alone — they move into existing tissues and manipulate surrounding normal cells to create what scientists call a “metastatic niche,” a microenvironment that shelters and supports tumor growth.
“As tumors progress, cancer cells leave the original site and spread or metastasize to other organs where they seed new tumors,” corresponding author Xiang Zhang, the 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, said in a news release.
Understanding what makes those niches tick is central to developing therapies that can interrupt the process.
“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,” added Zhang, who also is a member of Baylor’s Dan L Duncan Comprehensive Cancer Center.
A New Tool: SAMENT
The team built a method called Sortase A-Based Microenvironment Niche Tagging, or SAMENT. Rather than looking at tissue samples in bulk, SAMENT zeroes in on the specific normal cells that physically touch cancer cells during metastasis.
“Our method allowed us to identify specific cells encountered by cancer cells during metastasis,” co-first author Fengshuo Liu, a graduate student in Baylor’s Cancer and Cell Biology Program who works in the Zhang lab, said in the news release. “The method, called Sortase A-Based Microenvironment Niche Tagging (SAMENT), selectively labels normal cells that come into direct contact with cancer cells.”
Using SAMENT across multiple cancer models — spanning bone, lung, liver and brain metastases — the researchers identified a shared pattern: pro-metastatic niches were consistently packed with macrophages, a type of immune cell, while being nearly devoid of T cells, which normally help the immune system attack tumors.
The Bone Surprise
Bone metastases revealed something researchers didn’t expect.
“However, bone metastases stood out,” Liu added. “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.”
Critically, ERα-active macrophages were absent from healthy bone tissue and from primary tumors elsewhere in the body. They were present, however, in bone metastasis samples from patients with breast, lung and kidney cancers — including male patients — suggesting this mechanism is neither cancer-type-specific nor limited to women.
The researchers traced how this happens: cancer cells shuttle fatty acids to nearby macrophages, likely via tiny particles called extracellular vesicles. Those fatty acids trigger a metabolic pathway that activates ERα in the macrophages. Once activated, the macrophages flip from fighting cancer to protecting it — forming a physical and chemical barrier that keeps T cells from reaching the tumor.
Blocking ERα Slows Metastasis
To confirm that ERα in macrophages was driving bone metastasis, the team genetically deleted the ERα gene from macrophages in mice.
“To test whether ERα in macrophages can drive bone metastasis, we genetically removed the ERα gene specifically from macrophages in mice,” added Liu. “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.”
The team also tested fulvestrant, an FDA-approved drug already used to treat hormone receptor-positive breast cancer that works by degrading estrogen receptors.
“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 added. “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.”
What This Means for Patients
The potential to repurpose an existing, FDA-approved drug is significant. Fulvestrant is already prescribed and has a known safety profile, which could accelerate its path to clinical trials for bone metastasis treatment in a broader patient population than currently targeted.
For college students studying biology, medicine or pharmacology, this study also illustrates the value of developing new research tools — SAMENT itself may prove useful well beyond this single study, giving scientists a sharper lens for understanding the tumor microenvironment across many disease contexts.
Source: Baylor College of Medicine