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Mary Ellen Hackett
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Two scientists and their colleagues have uncovered a key activity driving a rare and deadly type of kidney cancer called hereditary leiomyomatosis and renal cell carcinoma (HLRCC). 


Their study explains how altered metabolism “rewires” these cancer cells, allowing them to be more aggressive and malignant. 

The new information illuminates a previously unknown aspect of HLRCC biology and may be useful for treatment, said Dan Crooks, Ph.D., a staff scientist who works in the National Cancer Institute’s (NCI) Urologic Oncology Branch. 

Crooks and Nunziata Maio, Ph.D., a staff scientist at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), worked with a large multidisciplinary team spanning NCI, NICHD, Frederick National Laboratory for Cancer Research (FNL), the National Institutes of Health Clinical Center, and University of Kentucky. 

“It’s a huge effort. It takes kind of an army to do this study,” said Crooks, who began working on the project in 2014. 

A missing enzyme and a metabolic defect 

Encouraged by W. Marston Linehan, M.D., Urologic Oncology Branch chief and the principal investigator on the study, Crooks set out to solve a mystery of metabolism in HLRCC. (Cellular metabolism is the process by which cells convert enzymes and chemicals into other enzymes and chemicals to create energy.) 

The mystery had two leads, a pair of abnormalities in metabolic function that suggested something was going awry. First, HLRCC cells have a mutation that makes them lack an enzyme called fumarate hydratase. Second, despite forming in an oxygen-rich environment, the tumors rely on a metabolic process called glycolysis—usually used in low-oxygen environments—to generate energy. 

Hooks and clues 

Thinking that a mutation in the HLRCC cells’ genes for metabolism might be at fault, the team first looked for clues of DNA alterations. But there were no relevant mutations—until the team broadened its search. 

There is more than one kind of DNA in human cells. The type most people think of is nuclear DNA, DNA housed in the nucleus—the “headquarters”—of the cell, but there’s also DNA in mitochondria, the cellular “power plants” and primary players in metabolism. Sevilay Turan and colleagues in the Sequencing Facility at FNL analyzed RNA made from the cells’ mitochondrial DNA, quickly noticing that there was much, much less than there should have been. 

“Then we had a bit of a hook,” Crooks said. The decreased RNA suggested that something was wrong with the mitochondrial DNA, and it could be forcing the cells to switch to glycolysis. 

From there, the team took a closer look at mitochondria and mitochondrial DNA in five sets of cells. The cells shared a substantial decrease in the biological machinery for respiration, the standard oxygen-consuming metabolic process. Electron microscopy performed by Ferri Soheilian in the Electron Microscopy Laboratory at FNL also revealed striking defects in the mitochondria’s structures, suggesting a genetic issue. 

“Looking at these tumors by electron microscopy was very eye-opening,” Crooks said. 

Meanwhile, Crooks; Martin Lang, Ph.D., a postdoctoral fellow at NCI at the time; and Turan performed genetic analyses showing that three sets of cells lacked much of their mitochondrial DNA, with the remaining DNA peppered with mutations affecting the cells’ use of oxygen in metabolism. The DNA was completely missing in the other two sets of cells. Bioinformatics analysis by Mayank Tandon, Ph.D., and Parthav Jailwala in the Advanced Biomedical Computational Sciences group in FNL’s Biomedical Informatics and Data Science Directorate, a collaborative body with robust informatics resources, further clarified the genetic data. 

The team closed in on cracking the mystery. Genetic trauma was at fault, but something was causing it. They considered other diseases driven by a loss of mitochondrial DNA, many of which are caused by problems with the proteins responsible for protecting the DNA’s integrity. 

NICHD’s Maio extracted those proteins from two sets of the HLRCC cells. One, called POLG, was defective, and the damage was associated with alterations caused by high levels of an enzyme called fumarate. Fumarate is managed by fumarate hydratase, the same enzyme that’s largely absent in HLRCC. 

The case cracked 

The team had its answer. The lack of fumarate hydratase enzyme causes a buildup of fumarate that damages POLG. The defective POLG fails to protect mitochondrial DNA, allowing it to gain mutations or become lost altogether. That eventually “rewires” the cells to switch to glycolysis, which lets them become more malignant. 

Importantly, further tests showed that correcting the fumarate hydratase mutation and putting the enzyme back into the cells doesn’t fix them. This lack of response is a feature that’s largely unique to these cells and potentially exploitable with cancer treatment. For instance, it may be possible to develop a compound that specifically targets these cells based on the missing enzyme and their inability to recover it. 

“There might be an edge there, where if we find a therapy which really exploits the loss of the respiratory chain as a weakness, we may have something there,” Crooks said. 

‘A pleasure to work’ 

Crooks added that the project was challenging and a “long, convoluted route,” but it was also fun and the largest team effort of his career. He spoke highly of all the collaborators, including the teams in Frederick. 

“I can’t underscore how much our colleagues at … Frederick contributed to this study,” he said. 

For their part, his colleagues at FNL felt similarly. 

“I was happy to be able to take part through electron microscopy,” said Soheilian.  

Turan said, “I love being involved in cancer research. … It was a great pleasure to work with a group of remarkable people.” 

Tandon agreed. 

“I haven’t even met half the people on this, but it’s pretty fantastic to do it,” he said. 


By Samuel Lopez, staff writer; image contributed by Dan Crooks