A study co-led by the Institute for Systems Biology (ISB) announced on April 10 reveals that some lung cancers are able to shift their cellular identity as they develop, making them more aggressive and harder to treat. The research, published in Cell Reports Medicine, focuses on combined small-cell lung cancer (cSCLC), a rare form of lung cancer with characteristics of both small-cell and non-small-cell types.
This discovery is significant because cSCLC tumors are often treated as standard small-cell lung cancer, despite patients having worse outcomes. The study shows that these mixed tumors originate from a single ancestral cell rather than two separate cancers. Over time, the cells within these tumors transition between different 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 researchers used spatial and single-cell genomic techniques to analyze tumor samples. They discovered that about one-third of SCLC-like tumor cells exist in hybrid states carrying features from multiple cancer types at once. This suggests that progression is not just a simple switch but rather occurs along a continuum.
Additionally, the team observed distinct microenvironments within individual tumors—some regions were filled with immune cells while others were largely excluded from immune response. These areas were often separated by dense bands of fibroblasts which could act as barriers against immune attack.
Qihui Shi, PhD from Fudan University and co-corresponding author said: "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... 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 improve identification of mixed-type tumors even when only one region is sampled during biopsy.
The findings underline the need for better understanding how cancer evolves over time—not just its genetic mutations but also changes in cellular state and interactions with surrounding tissue environments. "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."
