Cigarette smoke may need to damage lung cells well before a cancer-driving mutation ever appears in order for a tumor to take hold, according to a new study from Johns Hopkins University's Sidney Kimmel Comprehensive Cancer Center. The research, published Oct. 5 in the Proceedings of the National Academy of Sciences, is peer-reviewed but was conducted entirely in lab-grown lung tissue and mice — not in people — a distinction worth keeping in mind before drawing conclusions about human smokers.
The team built lung organoids, miniature three-dimensional tissue structures grown from normal mouse and human lung stem cells, and exposed them to cigarette smoke condensate for as long as six months. Afterward, researchers introduced one of two cancer-associated genetic changes — a KRAS mutation or the loss of the tumor-suppressor gene TP53 — into both smoke-exposed and unexposed organoids, then implanted the tissue into mice to see whether tumors would form.
Two Mutations, Two Different Cancers
Neither smoke exposure nor the genetic alterations alone produced tumors on their own, according to the Johns Hopkins summary of the findings. Only organoids that had been chronically exposed to smoke and then acquired one of the mutations went on to form tumors after implantation. The two mutations sent the tissue down distinct paths: KRAS mutations produced adenocarcinomas arising from bronchioalveolar stem cells, while TP53 loss produced squamous cell carcinomas arising from a separate population of basal stem cells. The researchers also found that prolonged smoke exposure suppressed inflammatory and immune signaling pathways, including a gene called ZBP1, potentially helping damaged cells evade the immune system's early warning response.
"What we have tried to do is model lung cancer from its very earliest stages," said Michelle Vaz, an instructor in oncology at Johns Hopkins and the study's senior author. Stephen Baylin, the Virginia and D.K. Ludwig Professor of Oncology and the study's co-senior author, framed the significance of the sequencing: "the genetic event alone is not sufficient" to trigger cancer, he said — the smoke-induced priming has to come first.
The finding builds on years of Johns Hopkins research showing cigarette smoke leaves behind epigenetic marks — chemical changes that alter gene activity without changing the underlying DNA sequence — well before any cancer-driving mutation appears. Because those marks have been shown in earlier work to be at least partly reversible after quitting smoking, the researchers see a potential window for intervention, though that remains speculative pending further study. The authors caution that validating the two mutation-specific pathways, and any markers or therapies derived from them, will require further testing beyond the organoid-and-mouse system used here. The underlying samples and sample sizes used in the organoid experiments were not detailed in the published summaries, another reason the team describes this as early-stage, mechanistic work rather than a clinical finding.
