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Wednesday, 7 October 2026dailybeirut.com
Health
A Johns Hopkins study reveals chronic cigarette smoke exposure reprograms lung stem cells, making them susceptible to specific genetic mutations that trigger distinct cancer types.
Chronic exposure to cigarette smoke may fundamentally alter the function of lung stem cells, rendering them more prone to transforming into cancerous cells when specific genetic mutations occur. This finding comes from a recent study conducted by researchers at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University.
The research indicates that the type of lung cancer that develops is not determined solely by genetic mutations. Instead, it is also influenced by the specific cell type in which the mutation occurs and its condition following continuous exposure to tobacco smoke. To investigate this, scientists utilized three-dimensional laboratory models known as "lung organoids." These miniature structures mimic certain characteristics of actual lung tissue.
Researchers exposed these organoids to cigarette smoke condensate—a mixture of chemicals and particles found in smoke—for six months. They then monitored the changes occurring within the cells. The team discovered that long-term smoke exposure triggered shifts in gene activity and control mechanisms. This led to the emergence of cellular states resembling those that precede cancer development. Additionally, natural defense mechanisms within the cells changed, including pathways associated with inflammation, immune response, and cell death.
Following the initial exposure phase, the scientists tested the impact of two mutations linked to lung cancer: the KRAS mutation and the loss of the tumor-suppressor gene TP53. Experiments revealed that tumors formed only when prior exposure to cigarette smoke combined with one of these genetic alterations. Neither smoke exposure alone nor the introduction of mutations into cells that had never been exposed to smoke resulted in tumor formation.
Dr. Michelle Fazio, the study’s lead author, stated, “What this tells us is that the genetic event alone is not enough.” The researchers emphasize that chronic smoke exposure first changes the state of the cells, making them more susceptible to malignant transformation once specific mutations arise.
A key outcome of the study was that different mutations led to different types of lung cancer. In organoids previously exposed to smoke, the KRAS mutation resulted in tumors with characteristics similar to lung adenocarcinoma. Conversely, the loss of TP53 produced tumors resembling squamous cell carcinoma. The team traced the origin of these tumors to distinct groups of stem cells. Tumors associated with the KRAS mutation appeared to originate from alveolar bronchial stem cells, while squamous tumors resulting from TP53 loss were linked to basal stem cells, which help maintain and repair the lining of the airways.
“It was very interesting that when we introduced the KRAS mutation or caused the loss of TP53, each seemed to select a specific state of stem cells,” Fazio said.
The findings suggest that chronic cigarette smoke exposure may not increase cancer risk merely by causing genetic mutations. It may also reshape cells and alter how they respond to mutations that appear later. Researchers believe that understanding these early changes could help identify molecular markers to detect individuals most vulnerable to lung cancer. Furthermore, this knowledge may reveal new targets for prevention and treatment strategies.
