SEATTLE — A new study co-led by the Institute for Systems Biology (ISB) shows that some lung cancers can change identity as they evolve, shifting from one cancer type to another in ways that may make them more aggressive and harder to treat.
The findings, published in Cell Reports Medicine , focus on a rare form of lung cancer known as combined small-cell lung cancer (cSCLC), in which tumors contain features of both small-cell and non-small-cell lung cancer. These mixed tumors are often treated as standard small-cell lung cancer, even though patients tend to have worse outcomes.
Using a combination of spatial and single-cell genomic approaches, the researchers found that these tumors do not arise from two separate cancers. Instead, they originate from a single ancestral cancer cell and evolve over time, with cells transitioning between identities.
"We found that these tumors are not simply mixtures of different cancer types," said Wei Wei, PhD , associate professor at ISB and co-corresponding author of the study. "They are dynamic systems, with cancer cells actively changing their identity. That flexibility may help explain why they are so difficult to treat."
The study also revealed that tumor cells can exist in intermediate or hybrid states, carrying features of multiple cancer types at once. About one-third of the SCLC-like tumor cells analyzed showed these mixed identities, suggesting that cancer progression is not a simple on-off switch, but a continuum.
In addition, the researchers found that different regions within the same tumor create distinct microenvironments. Some areas were rich in immune cells, while others were largely immune-excluded. Dense bands of fibroblasts — connective-tissue cells that tumors can co-opt to build protective barriers — often separated these regions. Those fibroblast-rich boundaries may help wall off parts of the tumor from immune attack.
"By combining spatial genomics, single-cell analysis, and multi-region sequencing, we were able to trace how these tumors evolve across both space and time," said Fudan University's Qihui Shi, PhD, co-corresponding author of the study. "This approach allowed us to capture transitional cell states that are not visible using conventional methods."
The team also developed a four-gene diagnostic tool, called cSCLC Detector, which may help identify these mixed tumors more accurately. The tool was built on a key insight from the study: although the small-cell and non-small-cell parts of cSCLC can look very different under the microscope, they come from the same ancestral tumor and share early trunk mutations. That means a biopsy that samples only the small-cell-looking region can still carry genetic clues that reveal the tumor's hidden mixed identity. In datasets of patients previously diagnosed with standard small-cell lung cancer, the tool detected a substantially higher proportion of cases with combined features, suggesting the disease may be underdiagnosed.
The findings highlight the importance of understanding not just the genetic mutations in cancer, but also how cancer cells change state and interact with their environment.
"Cancer is not static," Wei said. "To treat it effectively, we need to understand how it evolves — not just what it is at a single point in time."
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