Metastatic cancer begins when a cell from a primary tumor establishes itself in a new tissue. Tumors shed a lot of cells; fortunately, most of those disseminated cells die rather than take root in a new home. Researchers from universities and hospitals in China have found a metabolic and epigenetic state that sets apart the tiny subset of those cells that survive (Science 2026, DOI: 10.1126/science.adz7928).
Tumors’ survival depends on a complex interplay between mutant cells and their surrounding tissue—which can be difficult to map with bulk or dissociated single-cell analytical methods. Instead, researchers from Zhongshan Hospital, ShanghaiTech University, Fudan University, and BGI Research studied metastasis in mice using spatial transcriptomic analysis. “Our goal was to preserve the structural architecture and local microenvironment niches of the tissue,” writes co-corresponding author Yunfan Sun, a physician-scientist focused on liver cancer at Fudan University, in an email to C&EN.
The researchers injected tumor cells into mice and watched for over a month as metastases formed in the animals’ lungs. They found that the tumor cells rapidly seeded the lung, but a swarm of immune cells amassed within hours to clear them out.
The vanishingly rare survivors were the ones that interested the researchers.
There were many up- and downregulated genes in those surviving tumor cells. One key gene that the team identified as upregulated encodes the enzyme phosphoglycerate dehydrogenase (PHGDH), a rate limiter in single-carbon metabolism. PHGDH touches many cellular processes, but the team identified a specific histone methylation that appeared more frequently in the high-PHGDH cells. That epigenetic mark clustered on immune signaling genes, thus suppressing their expression. As a result, Sun writes, disseminated cells “effectively prevent the recruitment of cytotoxic . . . cells, creating an ‘immune-scarce’ sanctuary that allows them to survive initial host clearance.”
“What makes this finding surprising is the transient and non-proliferative nature of PHGDH elevation,” writes Wenkai Ren, a professor at South China Agricultural University who studies the interaction between metabolism and immunity, in an email to C&EN.
Because PHGDH also supplies metabolites for DNA synthesis, Ren says, one might expect fast growth from cells with high PHGDH. Instead, these cells were quiescent. Like a submarine seeking to evade detection, they had gone silent. And analysis of their neighborhoods showed that it was effective: they were surrounded by fewer immune cells.
Even though PHGDH expression dropped away as the stealthy survivor cells began to proliferate, Sun and colleagues showed using lineage tracing that most metastases descended from cells that had briefly had high PHGDH. They also explored the contribution of a subset of immune cells called macrophages to building a welcoming niche for these secondary tumors to grow.
According to Ren, the study’s strength is its demonstration that “distant tumor colonization is not a single event, but rather a complex and dynamic process.” That process involves many genes expressed in numerous cell types. But with a clearer understanding of the critical windows in the formation of secondary tumors, the researchers say they hope to find points where medicine can intervene.
