FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer

Autor: Veronika K Belova, Shrivatsav Pattabiraman, Eric L. Snyder, Timothy L. Mosbruger, Soledad A. Camolotto, Alex Jones, Klaus H. Kaestner, Grace Orstad, Chris Stubben, Lydia Salmond, Mitchell Streiff
Rok vydání: 2018
Předmět:
0301 basic medicine
Lung Neoplasms
Mouse
Cellular differentiation
Thyroid Nuclear Factor 1
Tumor initiation
Mice
Tumor Cells
Cultured
Biology (General)
Cancer Biology
General Neuroscience
Transdifferentiation
Cell Differentiation
General Medicine
respiratory system
3. Good health
Gene Expression Regulation
Neoplastic
medicine.anatomical_structure
Cell Transformation
Neoplastic
Phenotype
Carcinoma
Squamous Cell
Hepatocyte Nuclear Factor 3-beta
Medicine
Adenocarcinoma
NKX2-1
Research Article
Human
Hepatocyte Nuclear Factor 3-alpha
QH301-705.5
Adenosquamous carcinoma
Science
Adenocarcinoma of Lung
Mice
Transgenic
Biology
General Biochemistry
Genetics and Molecular Biology
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
Stomach Neoplasms
medicine
Biomarkers
Tumor
Cell Adhesion
Animals
Humans
lineage switching
Lung cancer
Lung
General Immunology and Microbiology
FoxA1
FoxA2
medicine.disease
Survival Analysis
Disease Models
Animal
lung cancer
030104 developmental biology
Cancer cell
Cancer research
Zdroj: eLife
eLife, Vol 7 (2018)
ISSN: 2050-084X
Popis: Changes in cancer cell identity can alter malignant potential and therapeutic response. Loss of the pulmonary lineage specifier NKX2-1 augments the growth of KRAS-driven lung adenocarcinoma and causes pulmonary to gastric transdifferentiation. Here, we show that the transcription factors FoxA1 and FoxA2 are required for initiation of mucinous NKX2-1-negative lung adenocarcinomas in the mouse and for activation of their gastric differentiation program. Foxa1/2 deletion severely impairs tumor initiation and causes a proximal shift in cellular identity, yielding tumors expressing markers of the squamocolumnar junction of the gastrointestinal tract. In contrast, we observe downregulation of FoxA1/2 expression in the squamous component of both murine and human lung adenosquamous carcinoma. Using sequential in vivo recombination, we find that FoxA1/2 loss in established KRAS-driven neoplasia originating from SPC-positive alveolar cells induces keratinizing squamous cell carcinomas. Thus, NKX2-1, FoxA1 and FoxA2 coordinately regulate the growth and identity of lung cancer in a context-specific manner.
eLife digest 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.
Databáze: OpenAIRE
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