Triple-negative breast cancer is more likely than many other breast cancers to spread to the brain, where treatment options are limited, and outcomes are often poor. The researchers identified a possible contributor in SIRP, a protein best known for regulating immune cells. Their experiments suggest that it also works inside cancer cells, changing both their behavior and the response of the brain’s immune defenses. Across several preclinical models, reducing or blocking SIRP slowed tumour growth, decreased the amount of cancer in the brain, and delayed the development of brain metastases, tumours formed by cancer spreading from elsewhere.
It also reversed some of the changes that helped cancer cells evade the immune response. “The biology of brain metastasis is incredibly complex, and we urgently need better ways to prevent and treat it. Our findings suggest that SIRP helps make tumor cells more aggressive while also changing the brain environment in ways that help those cells survive,” said corresponding author and associate professor of Cancer Biology at Wake Forest University School of Medicine, Dr. David R. Soto-Pantoja. Triple-negative breast cancer, or TNBC, is an aggressive disease that lacks three common markers used to guide treatment.
Analysing human breast cancer data and patient tumor samples, the researchers found elevated SIRP levels in TNBC cells, especially in tumors that had reached the brain, and linked higher levels to poorer patient outcomes. To investigate the biology behind those observations, the team conducted experiments involving breast cancer cells, immune cells, and mitochondria, the structures that produce energy within cells. Their preclinical models were designed to reproduce breast cancer’s spread to the brain. The study, by Tsai YT and colleagues, was recently published in Neuro-Oncology.
The experiments showed that SIRP increased cancer cells’ production of fibronectin, a protein that provides structure and support around cells. Repeated exposure to fibronectin appeared to reduce the ability of microglia, immune cells that help protect the brain, to trigger inflammation and attack the cancer cells. “One of the most intriguing findings was that the tumor cells appeared to weaken the response of the brain’s immune cells. “This creates a more favorable environment for cancer cells to grow and survive, and SIRP appears to play an important role in that process,” Soto-Pantoja said.
In cancer cells with high levels of SIRP, mitochondria broke into smaller pieces through a process called mitochondrial fission. This change made the cells more mobile and more likely to spread in the study models. Most experimental treatments involving the CD47-SIRP signaling pathway have focused on its role in immune cells. The findings suggest that targeting SIRP could also interfere with processes inside cancer cells, potentially offering an additional treatment effect.
Understanding the connections among cancer cells’ energy-producing machinery, their surrounding structural environment, and the brain’s immune response could inform research for patients whose TNBC has spread or is at high risk of spreading to the brain. The results remain preclinical, and additional studies are needed before this approach can be evaluated in patients. The investigators plan to examine how SIRP functions inside cancer cells, whether it can be targeted safely, and whether blocking it could improve the effects of existing immunotherapies or other treatments for TNBC brain metastases.
