Understanding the cellular processes that underlie the development of early-stage lung adenocarcinoma (LUAD) is necessary to design interventions. Recently, in a research report titled "An atlas of epithelial cell states and plasticity in lung adenocarcinoma" published in the international magazine Nature, scientists from the University of Texas MD Anderson Cancer Center and other institutions have constructed a new map of lung cells through research. The study reveals new cellular pathways and precursors in the development of lung adenocarcinoma, and related findings may help develop new strategies to detect or block the progression of the disease at an early stage.
Lung adenocarcinoma is the most common form of lung cancer. In this study, the researchers used single-cell sequencing technology to study the genetic changes in each cell, and finally generated a cell map of approximately 25 normal and cancerous epithelial cells. One of the key findings of this multidisciplinary study was the discovery and validation of a transitional alveolar cell state harboring KRAS mutations, even in normal lung cells, that ultimately transforms into lung adenocarcinoma. Alveolar cells are epithelial cells in the lungs that are important for gas exchange and include two cell types. Type I cells are more common and their main function is responsible for gas exchange. There are fewer type II cells, which can provide support for type I cells to function. In the event of lung injury, type II cells possess inherent properties that promote their differentiation into type I cells to replace damaged cells. According to the researchers, this transition process can be intercepted, resulting in a different cell fate in these converted type II cells.
"We have studied a large number of epithelial cells, and combined with new technologies, we may be able to identify two different fates of type II cells," Researcher Kadara said. "They share common intermediate states, but one pathway leads to type I cells, while the other leads to tumor progression. Consciously, we even find these cells in an intermediate state in normal lung tissue and in normal areas around lung cancer, where they get trapped. If the process was short-lived or a rapid transition, we might not find so many cells, but it is there."
The researchers also found that these intermediate cells in normal tissues (not yet cancerous or even precancerous) may carry KRAS driver mutations. These mutations were not present in other cell types but matched the same patient's tumors. Extensive sequencing previously established KRAS mutations in normal tissue. But using this new method and other computational tools, the researchers were able to determine that the mutations came from a specific type of cell and infer that they might be precursors to adenocarcinoma. But this still requires further research by researchers to analyze this transition process to more fully understand the mechanism at play. Using two- and three-dimensional multimodal and dynamic spatial imaging and molecular analysis, researchers are exploring the transition from normal epithelial cells to precancerous lesions and ultimately to invasive cancer during lung tumorigenesis. Now researchers have indeed found that these cell characteristics are present at higher levels in pre-lung cancers and lung adenocarcinomas.
To confirm the findings in vivo, the researchers used a model of exposure to tobacco carcinogens. This model produces lung damage similar to that of smoking, and the researchers speculate that smoking, which is often causally linked to lung cancer, stimulates a transitional state in alveolar cells by damaging lung tissue. Not only do these models exhibit cells in an intermediate state before any tumors or precancerous lesions develop, but these cells persist. The researchers found that cells in an intermediate state persisted for 6-7 months after carcinogen exposure ceased, the same as found in human cells. These intermediate cells also carry KRAS mutations and express features of KRAS activation. In fact, when researchers used these cell types to generate organ models or organoids in vitro, they found that cells in these intermediate states were more responsive to KRAS inhibitors.
"Our study provides clear evidence that tumor cells are indeed generated from cells in these intermediate states, which opens the door to new research in the future," said researcher Kadara. These findings also make researchers very excited because they show that KRAS inhibitors can produce certain therapeutic benefits in clinical therapy and can even effectively block the original stage of lung adenocarcinoma. The researchers are currently working together to explore whether combination therapies can be used to target these cells and to investigate the molecular mechanisms underlying their transformation into lung adenocarcinoma, including inflammation. These early transformations may be significantly affected by the surrounding tumor microenvironment.
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Comprehensive understanding of the dynamic interactions between these cells and the immune microenvironment through in-depth spatial analysis may provide key clues and ideas for early detection of diseases and the development of novel interception strategies. In summary, the results of this study also provide new research insights for elucidating the epithelial cell status of lung adenocarcinoma. These states may be expected to help identify potential targets for the development of novel preventive or interventional strategies.
Reference
Han G, et al. An atlas of epithelial cell states and plasticity in lung adenocarcinoma. Nature, 2024: 1-8.