Chronic smoke exposure alters lung repair cells and helps decide which form of the disease develops after genetic mutations occur.
RT’s Three Key Takeaways:
- Cellular Priming: Chronic exposure to cigarette smoke alters lung stem cells epigenetically, creating a precancerous state that enables cancer-driving genetic mutations to form tumors.
- Subtype Selection: The specific form of non-small cell lung cancer depends on both the mutation and the cell state, with KRAS alterations leading to adenocarcinoma in bronchioalveolar cells and TP53 loss driving squamous cell carcinoma in airway basal cells.
- Therapeutic Targets: Identifying the cell death pathways and epigenetic shifts caused by smoking may help healthcare researchers develop targeted therapies and early prevention strategies.
Chronic exposure to cigarette smoke reprograms distinct populations of lung stem cells, making them vulnerable to specific cancer-causing gene alterations and ultimately helping determine which type of lung cancer develops, according to a study published in the Proceedings of the National Academy of Sciences.
The findings offer new insight into how environmental exposure, epigenetic changes, and genetic mutations interact during the earliest stages of non-small cell lung cancer (NSCLC), the most common form of the disease.
“What we have tried to do is model lung cancer from its very earliest stages,” said Michelle Vaz, PhD, instructor in oncology and senior author of the study, in a news release. “Using these organoid models, which are rich in stem cells, we were able to follow the cells over six months of exposure and see the epigenetic and gene expression changes occurring in these different stem cell types.”
Modeling Early Cellular Changes
To study how normal lung tissue becomes cancerous, researchers created three-dimensional lung organoids from normal mouse lung tissue and exposed them to cigarette smoke condensate for up to six months, while also confirming key early findings in organoids derived from normal human lung tissue.
Over time, the smoke exposure altered the balance and behavior of the cells, driving them into a precancerous state, according to the study. Investigators identified progressive shifts in DNA methylation and chromatin accessibility, which regulate gene activity and expression. Among the primary alterations was the suppression of inflammatory and immune signaling pathways, as well as genes involved in programmed cell death, including ZBP1, a key regulator of inflammatory cell death.
Investigators then tested whether smoke exposure made the organoids susceptible to cancer-driving mutations by introducing mutant KRAS or knocking out the tumor suppressor gene TP53 into both exposed and unexposed organoids, which were then implanted into mice.
Only the smoke-exposed organoids containing a genetic alteration formed tumors, according to the research team. Cigarette smoke exposure alone did not produce tumors, and introducing the genetic mutations into unexposed control organoids also failed to generate tumors.
“What this tells us is that the genetic event alone is not sufficient,” said Vaz. She and co-senior author Stephen Baylin, MD, professor of cancer research and co-director of the cancer genetics and epigenetics program, noted that cells must first undergo changes caused by chronic smoke exposure before becoming susceptible to cancerous conversion.
Stem Cell Lineages and Cancer Subtypes
The study demonstrated that genetic alterations produced two distinct forms of NSCLC based on specific stem cell states. Smoke-exposed organoids with mutant KRAS developed poorly differentiated cancers with features of lung adenocarcinoma, while smoke-exposed organoids lacking TP53 developed squamous cell cancers.
Using single-cell RNA sequencing, researchers traced KRAS-driven adenocarcinomas back to an altered cell state derived from bronchioalveolar stem cells, which reside where airways connect to the alveoli. Conversely, TP53-deficient squamous cell carcinomas arose from basal stem cells, which maintain and repair the lining of the airways.
“It was very interesting that when we introduced KRAS or loss of TP53, each seemed to select for a particular type of stem cell state,” said Vaz, in a news release. “We did not engineer the genetic event into a particular cell type. This is what the mutations selected for.”
Clinical and Therapeutic Implications
The study noted that silencing of ZBP1 and related interferon signaling was pronounced in KRAS-mutant tumors, suggesting that the loss of these defenses may enable KRAS-driven cancer cells to survive. Analysis of human lung adenocarcinoma data confirmed significantly lower expression of ZBP1 and related interferon pathway genes in tumors with KRAS mutations compared to those with TP53 mutations.
According to the authors, these altered stem cell states could eventually serve as molecular markers to detect the early evolution of NSCLC subtypes, potentially aiding early identification and cancer prevention strategies for high-risk patients.
“What’s exciting as a next step is whether we can learn more about these cell death pathways and whether some can be targeted, specifically in the KRAS versus TP53 setting,” said Vaz, in a news release. “Can we combine that with epigenetic therapy or immunotherapy and help tumors that currently do not respond to treatment, respond better?”
