Cancer biologist leads team in unraveling cellular activity

Generations of high school students have memorized the basic phases of cell division — and more than likely forgotten them by the time summer rolls around. But as class after class has labored over its four distinct phases — G1, S, G2 and mitosis — researchers in the lab have been painstakingly adding to the body of knowledge of precisely how each phase is accomplished. By revealing what occurs when everything goes as planned, they also have shown how things can go awry. 

J. Alan Diehl, Ph.D., the SmartState endowed chair in lipidomics, pathobiology and therapy and associate director of basic sciences at the Hollings Cancer Center, has devoted his career to studying how a breakdown in normal pathways gives rise to cancer. The National Institutes of Health recently awarded Diehl an additional $1.6 million to continue the work he began in 2000. The grant will enable him to continue this work through 2023.

Research, he said, starts with a basic question: “How does this work?”

“What I tell students and postdocs is, if you ask a good, relevant question and you develop experiments that answer that question, you will see opportunities to translate this to treatments,” he said. 

However, you can’t necessarily predict where those treatment opportunities will arise, he said. 

“Sometimes, it’s not the enzyme itself; it’s something that it does. It triggers a vulnerability in the tumor cell that you would have had no idea was there unless you spent some time doing what appears to be very esoteric research, answering esoteric questions,” he said. 

The essence of his work is figuring out what controls the expression of particular proteins in a normal cell and what happens to those proteins in a cancer cell. His lab has found that these proteins take on new functions though their inherent actions haven’t changed. 

“It’s doing something that it shouldn’t do, and it’s doing that because it’s in the wrong place at the wrong time and not turned off when it should be,” he said. 

Proteins called cyclins – so named because they’re supposed to cycle through synthesis and degradation — function within the nucleus of a cell. Cyclin D1 helps regulate the G1 phase of cell division. When its work is done, it’s supposed to be ejected into the cytoplasm and destroyed. If it instead remains in the nucleus, it’s “turned on” indefinitely.

Cyclin D1 is well studied because it’s long been known to be dysregulated in multiple cancers, including metastatic breast cancer, head and neck cancers, endometrial and uterine cancers and mantle cell lymphoma.

In the past few years, the FDA has approved three new drugs that target the enzymes that partner with cyclin D1. The drugs are approved for certain types of metastatic breast cancer. 

Less well studied are cyclins D2 and D3. Diehl’s lab is looking at cyclin D3, and next year, he expects to publish a paper about its role. 

Cyclin D3 is mutated in patients with Burkitt lymphoma, but there’s no published data yet about whether the mutation is a result of the cancer or is causing the cancer. The only clue is that cyclin D1 is cancer causing when it has a similar mutation. Researchers are studying how the accumulation and loss of cyclin D3 is regulated – how it turns on and off and why it’s mutated more often in Burkitt lymphoma than in mantle cell lymphoma.

Once researchers understand the regulators of cyclins D2 and D3, they can start building models of diseases, and from there develop better treatments. 

Scientists have learned so much just by doing good, fundamental cell biology and biochemistry research, Diehl said. 

While he can’t predict what the next cancer-fighting drug will be, he said he can ask questions and recognize opportunities. 

“You can’t always predict where those are going to be without doing the experiments and learning,” he said.