Lung adenocarcinoma is a type of non-small cell lung cancer (NSCLC) that arises from the bronchial mucosal glands. It represents about 40% of all lung cancers and is the most common NSCLC in the U.S.
Patients with non-small cell lung cancer are usually treated with chemotherapy, surgery, targeted therapy, radiation therapy, or a combination of these treatments. In devising intervention strategies for this disease, it is important to understand the cellular processes that underlie this condition.
Hijacked Lung Cells
Our lungs contain two types of alveolar cells or the epithelial cells involved in gas exchange inside the lung. Type I cells are primarily involved in the gas exchange, while type II cells are those that provide support for this process. When the lung gets injured, the inherent properties of type II cells enable them to differentiate into type I cells to replace damaged cells.
This transition process can be "hijacked" and lead to a different fate for some transitioning type II cells. Two things can happen to type II cells. Although they share a common intermediate state, one path leads to type I cells, and the other can progress to tumors.
Interestingly, these intermediate cells can be found in normal lung tissue as well as in normal regions that surround lung cancers. Experts may not see them if they quickly transition, but they are just stuck.
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Unveiling Cellular Pathways
At the University of Texas MD Anderson Cancer Center, researchers created a new atlas of lung cells to understand better the cellular pathways and precursors in lung adenocarcinoma development. Their findings, described in the paper "An atlas of epithelial cell states and plasticity in lung adenocarcinoma," offer new opportunities in developing novel strategies for detecting or intercepting the disease in its earliest stages.
Professor Humam Kadara of Translational Molecular Pathology and Associate Professor Linghua Wang of Genomic Medicine leads the research team. They generated about 250,000 normal and cancerous epithelial cells that line the lungs. This was done by individually studying genetic changes in each of these cells with the help of single-cell sequencing technology. One of the key findings of this multidisciplinary work was the discovery and validation of a transitional alveolar cell state that nurtures KRAS mutations.
In previous studies, bulk sequencing was found to establish KRAS mutations in normal tissue. When this new approach was used with other computational tools, the researchers discovered that KRAS mutations come from one specific cell type. As a result, they are assumed to be the precursors to adenocarcinoma.
To confirm their research findings, Kadara and his team used a model exposed to tobacco carcinogens. This creates damage in the lungs, like that stimulated by cigarette smoke. The team theorized that smoking can trigger the alveolar transitional state by "injuring" the lung tissue.
According to the researchers, their findings suggest that KRAS inhibitors can be clinically beneficial for treating interception of early cases of lung adenocarcinoma. Currently, Kadara and Wang plan to target lung cells with combination therapies and explore the mechanisms of their transformation to lung cancer.
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