Two key drivers of hereditary kidney cancer are identified

An international research collaboration including scientists from the Frederick National Laboratory has identified two key drivers of a hereditary kidney cancer and opened new possibilities for therapeutic approaches to a disease whose current treatment is largely surgerical.  

The scientists implicated two proteins that work cooperatively to drive tumor formation in Birt-Hogg-Dubé (BHD) syndrome, an inherited cancer syndrome that causes benign skin lesions, lung cysts that can cause lung collapse, and kidney tumors.  

Results were reported in EMBO Molecular Medicine. Laura Schmidt and Baktiar Karim of the Frederick National Laboratory's Molecular Histopathology Laboratory were co-authors. 

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The research group conducted a series of experiments in animal models of BHD. First, they found that inactivating either of the two proteins – transcription factors TFEB and TFE3 – in kidneys of a genetically engineered BHD mouse model affected the extent of kidney cyst development. They concluded that the two proteins work together to cause disease since their ability to drive cystogenesis depended on how much of each protein was present in the kidney cell. Further investigation showed that tumors developed in mice injected with human BHD tumor cells, but not when TFEB or TFE3 was silenced in those cells. 

In studies with BHD kidney tissue obtained with consent from patients surgically treated at the National Institutes of Health Clinical Research Center, scientists compared tumors from BHD patients and normal kidneys. The tumors showed increased activity of TFEB, TFE3 and several of their target genes. Because both transcription factors regulate many genes, the scientists looked further. 

Comparative analysis of tumor samples from additional BHD patients and controls showed 229 of 2,402 statistically significantly upregulated genes were related to TFEB and TFE3, including many genes responsible for creating lysosomes. Lysosomes are involved in digestion, degradation, and waste disposal, keeping cells healthy and clean. Abnormal lysosome activity can affect cell proliferation and mortality, leading to out-of-control cell growth and proliferation, major hallmarks of cancer. 

Further analysis of the human BHD tumors identified 28 genes that were upregulated by TFEB and TFE3 but were downregulated in BHD kidney cancer cells in which TFE3 or TFEB expression was silenced. Shutting down several of these genes significantly reduced proliferation of BHD kidney cancer cells.  

Kidneys have over a dozen types of highly specialized epithelial cells, in addition to specialized endothelial, immune, and interstitial cells. How TFEB and TFE3 affect the health of these cells depends on the amount and activity of each protein. These complex relationships warrant further investigation, the scientists noted. 

Identifying molecules that could intermittently inhibit TFEB and TFE3 activity could lead to a potential therapy. 

BHD is a rare disorder caused by an inherited mutation in the FLCN tumor suppressor gene that leads to benign skin tumors, lung cysts and a heightened risk of kidney cysts and tumors. If the tumor is caught early, surgery may control its progression. By one estimate, BHD affects only two individuals per million. But because of the ubiquity of TFEB and TFE3 in the body, understanding their role in inherited kidney cancer could be relevant to other cancers and unrelated diseases such as Parkinson's and Alzheimer's.  

The research collaboration was led by Andrea Ballabio of the Telethon Institute of Genetics and Medicine in Pozzuoli, Italy, and Marston Linehan of the Urologic Oncology Branch at the U.S. National Cancer Institute.