Research News

A team of Cleveland Clinic researchers has discovered that our own white blood cells play a pivotal role in helping breast cancer metastasize to the brain. The PNAS article from the laboratory of Peiwen Chen, PhD, describes how breast cancer cells that travel to the brain shape the surrounding tissue to form a favorable tumor microenvironment, promoting metastasis and tumor growth. 

“There’s a real unmet need for patients whose breast cancer has spread to the brain because treatment options are extremely limited, and outcomes are usually poor,” says study lead author Fatima Khan, PhD, a postdoctoral fellow in Dr. Chen’s lab. “There’s been some evidence that the immune system in our body helps shape metastasis, so I wanted to know which immune cells are truly driving tumor growth and survival and how they were doing it.”  

Dr. Khan first analyzed publicly available cancer databases to look for key signaling pathway differences between primary breast tumors and brain metastatic breast tumors. 

She then used computational analysis, laboratory bench work and preclinical models to understand how tumors could develop brain metastasis. In doing so, she unraveled a complicated communication network between healthy and cancerous cells in our brains that drive breast cancer brain metastasis (BCBM).  

“These breast cancer cells aren’t just showing up in the brain and setting up shop in hostile territory,” Dr. Khan says. “They’re tricking the infiltrating healthy cells in our brains into making the environment welcoming and hospitable. It's less like a violent takeover and more like a manipulative conversation.” 

Here’s what Dr. Khan discovered happens when breast cancer metastasizes to our brains: 

• Breast cancer cells that reach the brain secrete molecules called MMP1 into the surrounding tissue.
• These secreted molecules reach brain-infiltrating white blood cells, which start making an immune-related molecule called TBK1.
• TBK1 “activates” the immune cells and tells them to work for the cancer metastasis. The pro-tumor white blood cells are called tumor-associated macrophages (TAMs).
• Activated TAMs then secrete molecules called GM-CSF into the brain tissue.
• GM-CSF goes back to the cancer cells and tells them how to migrate through, invade into and set up tumor residence in the brain, fueling metastatic outgrowth. 

Repurposed drugs may help treat breast cancer brain metastasis 

With each step the Chen Lab uncovered in the communication network between BCBM cells and TAMs in the brain, new potential drug targets emerged. Each target represented a point where the metastatic process could be interrupted. 

Blocking TBK1 in preclinical models proved especially powerful. It halted tumor growth, reversed metastasis and significantly extended survival. These results were seen with lab-only compounds and with Amlexanox, an FDA-approved drug that also inhibits TBK1 to treat canker sores. 

“If a drug is already approved for something else, we know a lot about its safety, so it’s much quicker and easier to move it into clinical trials for new indications compared to a brand-new drug,” Dr. Khan says. “Right now, we’re doing more testing with TBK1 inhibitors, including combinations with standard treatments. We hope to move into clinical trials soon.”