Tumor from mouse lung. Image credit: Camolotto et al. (CC BY 4.0)
Among all cancers, lung cancers cause the most deaths worldwide. There are many different types of lung cancer, each of which contain lung cancer cells that look different. As a general rule, lung cancer cells that look the most like healthy lung cells are the least aggressive. Cancer cells that take on the appearance of other tissues in the body are more aggressive and often respond poorly to treatment. In one uncommon type of lung cancer called invasive mucinous adenocarcinoma (IMA, for short), the cancer cells start to resemble the cells that line the inside of the stomach. For example, these lung cancer cells activate genes more typically active in stomach cells, and they start to make a lot of mucus.
Previous studies with mice showed that losing a single protein called NKX2-1 can cause this switch from lung to stomach cell identity. However, it is not clear exactly how this switch happens and which other proteins are involved. Camolotto et al. have now addressed these issues by studying two DNA-binding proteins called FoxA1 and FoxA2. There were two main reasons for choosing these specific proteins. First, they can physically interact with the NKX2-1 protein, so losing NKX2-1 affects how FoxA1 and FoxA2 interact with DNA. Second, the two proteins switch on many of the stomach-related genes that are also activated in IMA.
Camolotto et al. activated a gene that commonly drives lung cancer and deleted the gene for NKX2-1 in the lungs of mice, mimicking IMA. As expected, these mice developed lung tumors that resembled stomach tissue. When the genes for FoxA1 and FoxA2 were deleted at the same time, the tumors stopped producing the mucus-related proteins. Further experiments showed that these cancer cells adopt a different cell identity also found in the digestive tract. Mice with tumors lacking both FoxA1 and FoxA2 survived for longer than those still containing these proteins. Lastly, when the genes for NKX2-1, FoxA1 and FoxA2 were deleted later, in lung tumors that had already formed, the outcome was a more aggressive type of lung cancer that also occurs in human patients.
These experiments demonstrate that losing FoxA1 and FoxA2 at different times affects what kind of lung tumor can grow. Future studies will need to examine how these different lung cancer types respond to therapy and whether lung cancer cells switch identities to evade therapy. This knowledge may eventually lead to new treatments for lung cancer patients.
