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Mouse Model Sheds Light on How Lung Adenocarcinoma Can Transform into a More Aggressive Type of Lung Cancer


Initial treatments for lung adenocarcinomas may be effective at first, but sometimes these tumors can respond by turning into small cell lung cancer (SCLC), a more aggressive and difficult-to-treat disease.

Lung adenocarcinoma is the most common type of lung cancer, accounting for 40% of cases. It's a form of non-small cell lung cancer (NSCLC) that can occur in people with or without a history of smoking. Epidermal growth factor receptor (EGFR) mutations are the most common oncogenes in NSCLC, which drive cancer growth.

Initial treatments for lung adenocarcinomas may be effective at first, but sometimes these tumors can respond by turning into small cell lung cancer (SCLC), a more aggressive and difficult-to-treat disease.

Now, researchers at Weill Cornell Medicine have developed a mouse model that sheds light on the processes behind this transformation. Their findings, published in Science, may help identify potential targets for new, more effective treatments.

“Broadly, this study reinforces that not all oncogenes can transform any cell type into a cancer. Here, we use lung cancer as a model system and explore a phenomenon termed ‘histological transformation,’ Eric E. Gardner, Pharm.D., Ph.D., lead author of the study and a postdoctoral fellow at the Varmus laboratory at Meyer Cancer Center in Weill Cornell Medicine, told Managed Healthcare Executive.

Gardner explained that their study focused on histological transformation of EGFR-driven lung adenocarcinoma (LUAD) into small-cell lung cancer. “SCLC is an aggressive, recalcitrant cancer that spreads quickly. Currently, there are limited therapeutic options to treat and control SCLC. This may be – in part – due to a lack of a basic understanding as to how this cancer is fundamentally driven,” he said.

The researchers observed that during the transition from lung adenocarcinoma to SCLC, the mutated cells underwent a change in cell identity through an intermediate, stem cell-like state. This shift facilitated the transformation and highlighted the role of specific genes, such as Myc, in driving the process.

“Specifically, this study demonstrates that the oncogenes that drive these two different types of lung cancer are not only different but incompatible (i.e., toxic) when placed into the other type of cell,” Gardner stated.

“We use something called ‘lineage tracing’ where we have designed genetically engineered mice to activate different oncogenes (human or mouse) in different cell types in a very controlled manner. We can use these tools to study the impact certain oncogenes have on cell behavior in a completely intact (whole animal) system,” he explained.

“For example, we show that the oncogene Myc is sufficient to transform the pulmonary neuroendocrine cell (PNEC) lineage; however, when we express oncogenic Myc in the alveolar type II cell (the predominant cell of origin for LUAD), we do not observe transformation, but rather toxicity to this cell type – the cells die,” Gardner said.

These findings reveal new insights into the role of oncogenes and highlight the importance of considering cell type when developing targeted therapies. The researchers plan to further investigate the adenocarcinoma-SCLC transition and explore how the immune system responds to this transformation. Ultimately, their work could lead to more effective treatments targeting lung cancer.

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