Two-stage process helps metastatic cancer cells hide, then multiply in the lungs

Two-stage process enables metastatic cancer cells to hide and multiply in lungs, according to a new study published in Science. Researchers mapped the process of how liver cancer cells spread to the lungs in mice and found that this occurs in two distinct phases.

After the initial immune response, surviving tumor cells entered a slow-growing phase characterized by high dependence on the PHGDH enzyme. This state allowed them to evade immune detection by suppressing distress signals that would typically attract immune cells. By analyzing cell-tracing experiments, researchers discovered that most large metastases likely originated from cells that had briefly experienced the high-PHGDH state during early colonization.

After this initial phase, a second event unfolded where immunosuppressive macrophages accumulated in the tumor microenvironment. This recruitment of immune-suppressing cells, along with growth signals, enabled the dormant tumor cells to resume growth and undergo metastatic outgrowth. Inhibiting the high-PHGDH pathway or reducing macrophage populations in mice experiments led to reduced lung metastases, suggesting potential therapeutic targets for blocking these metastatic processes.

However, it's important to note that these findings were based on mouse models, specifically liver cancer spreading to the lungs. Future research will need to determine if this two-stage process occurs in other cancer types and metastatic organs, and whether the model fully translates to human cancer patients. The study authors emphasize the importance of developing therapies specifically targeting micrometastases, as their distinct signaling pathways and immune-evasive strategies differ from established macrometastases.