Researchers at University of Southampton have uncovered a key mechanism that allows lung cancer cells to become more aggressive and resistant to treatment by switching back to an earlier developmental state.
The findings, published in Molecular Oncology, provide new insights into why some lung cancer patients fail to respond to chemotherapy and immunotherapy, and may help pave the way for more personalised treatment strategies.
The study focused on lung adenocarcinoma, one of the most common forms of lung cancer. Scientists analysed tumour data from more than 1,500 patients using advanced multi-scale biological analysis techniques to better understand disease progression and therapy resistance.
The research team discovered that some cancer cells reactivate a developmental programme normally seen during early lung formation. In healthy lung development, the lungs initially grow through a branching process before later forming alveoli, tiny air sacs responsible for oxygen exchange.
According to senior researcher Chris Hanley, aggressive lung tumours appear to reverse this process.
“In some severe lung cancers, cells revert from their alveoli-forming state back to a branching state. This allows the cancer to grow faster and become more resistant to treatment,” Hanley explained.
The researchers found that measuring genes associated with this branching process could help predict how patients are likely to respond to therapy.
Further laboratory studies identified two major biological changes driving this transformation: loss of the tumour-suppressor gene TP53 and activation of interferon signalling, a pathway normally involved in protecting the body against viral infections.
Scientists observed that the combination of these mechanisms promotes cellular plasticity, the ability of cancer cells to change their identity and behaviour.
The study suggests that targeting these pathways could lead to future therapies designed to stop cancer cells from switching states and developing treatment resistance.
The researchers believe their findings could ultimately help doctors identify high-risk patients earlier and improve treatment selection based on tumour biology.
The study titled “Developmental programmes drive cellular plasticity, disease progression and therapy resistance in lung adenocarcinoma” is now available online in Molecular Oncology.
