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 tumours contain features of both small-cell and non-small-cell lung cancer.

These mixed tumours 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 tumours 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.

The study also revealed that tumour cells can exist in intermediate or hybrid states, carrying features of multiple cancer types at once.

About one-third of the SCLC-like tumour cells analysed 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 tumour create distinct microenvironments.

Some areas were rich in immune cells, while others were largely immune-excluded.

Dense bands of fibroblasts — connective-tissue cells that tumours can co-opt to build protective barriers — often separated these regions.

Those fibroblast-rich boundaries may help wall off parts of the tumour from immune attack.

The team also developed a four-gene diagnostic tool, called cSCLC Detector, which may help identify these mixed tumours 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 tumour 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 tumour’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.

Source: Institute for Systems Biology