How Cancer Seed Cells Evade the Brain’s Microglia

Metastasis happens when cancer cells leave the original tumor, circulate through the bloodstream, and establish new tumors elsewhere in the body, and it is the main cause of cancer-related deaths. Brain metastases are especially serious and occur in 10–30% of patients with advanced lung, breast, and melanoma cancers. Although treatments exist for established brain tumors, there are few approaches that directly address the earliest cancer “seed cells” that first lodge in the brain.

The brain’s resident immune cells, microglia, can quickly respond to pathogens and cancer cells by engulfing and digesting them. Until recently, it was unclear why microglia sometimes fail to eliminate incoming seed cells, largely because this interaction could not be observed in real time in the living brain. In a new study published in Cancer Research, investigators from Nagoya University visualized, for the first time in this context, the precise moment when microglia engulf seed cells attempting to colonize the brain. The work identifies two proteins that seed cells use to avoid destruction at this earliest stage, and shows that removing these proteins reveals the importance of microglia in clearing cancer cells as they arrive.

The team focused on seed cells traveling from the lung to the brain to understand how they behave upon entry, a roughly 12‑day window during which microglia can still eliminate them. By the time symptoms or imaging findings appear, this window has closed and tumors are already established. “We recorded the interactions between microglia and cancer cells in live mice using an advanced imaging technique called two-photon microscopy,” first author Takahiro Tsuji explained. Using a newly developed “opto-omics” method, the team selectively tagged, isolated, and analyzed only those microglia that were physically interacting with tumor cells to understand why some destroy cancer cells while others support their survival and growth.

The study shows that cancer cells arriving in the brain evade microglial destruction by deploying “don’t eat me” signals from two molecules, CD24 and CD47. When these molecules were genetically removed, microglia digested the seed cells and brain tumor formation was markedly reduced. CD24 and CD47 appeared in 50% of human brain metastasis samples from lung cancer patients, suggesting clinical relevance. Senior author Professor Hiroaki Wake noted that some microglia are reprogrammed to help tumors by promoting blood vessel formation and building a protective niche, and that understanding this divergence at first contact is essential for better therapies.

The researchers propose a strategy to eliminate seed cells by targeting CD24 and CD47 with antibodies or other approaches during the early stage when microglia can still phagocytose cancer cells. “This approach focuses on harnessing our brain's immune system to prevent metastasis at a very early stage, rather than treating tumors after they have already formed,” Tsuji said. The team is now working on therapies to remove CD24 and CD47, alone or in combination with existing treatments, and on biomarkers to identify patients who might benefit most from early intervention.