What is it about?
Small-cell lung cancer is one of the most aggressive and least understood cancers, with few advances in patient survival over the past 30 years. This study identifies Lamin A/C loss as a key driver of genetic instability, a hallmark of the disease that fuels rapid evolution and treatment resistance. We show that Lamin A/C–deficient tumors, which typically display strong neuroendocrine (NE) features, experience heightened replication stress because their distorted nuclear architecture compresses nuclear pores, restricting RNA export. This congestion leads to collisions between transcription and replication machinery, resulting in R-loop accumulation, DNA damage, and genome instability. By uncovering this mechanism, our work explains why high-NE SCLC tumors are especially aggressive and reveals new opportunities to target replication stress and improve patient outcomes.
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Why is it important?
Our research discovered that when cancer cells lose a protein called Lamin A/C, which helps keep their DNA organized and protected, they become much more unstable. This instability allows genetic errors to build up, making the cancer more aggressive. We found that tumors missing Lamin A/C are filled with tangled DNA loops, known as R-loops, that damage the cell’s genetic code. Patients whose tumors lacked this protein tended to have shorter survival. By revealing how loss of Lamin A/C drives DNA damage in small-cell lung cancer, this study points to a new way to identify high-risk patients and opens the door to treatments that could help stabilize cancer cells and improve patient outcomes.
Perspectives
What struck me most during this work was how a structural change in the nucleus, something as fundamental as the loss of Lamin A/C, could ripple outward to influence genome stability, replication, tumor phenotype, and how aggressively a tumor behaves. It connected physical cell architecture to the small-cell lung cancer behavior. It highlights how understanding the mechanical side of cancer cell biology can open new therapeutic directions for one of the most treatment-resistant cancers we face.
Anish Thomas
NIH
Read the Original
This page is a summary of: Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer, Proceedings of the National Academy of Sciences, October 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2503387122.
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