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Ute Moll

Ute Moll. Photo courtesy of Stony Brook University

By Daniel Dunaief

In the battle against cancer, human bodies have built-in defenses. Cancers, however, can hijack those systems, turning them against us, not only allowing them to avoid these protective systems, but converting them into participants in a process that can often become fatal.

Such is the case for the p53 gene. One of the most closely studied genes among researchers and clinicians, this gene eliminates cells with damaged DNA, which could turn into cancer. Mutations in this genetic watchdog, however, can turn this genetic hero into a villainous cancer collaborator. Indeed, changes in the genetic code for p53 can allow it to produce a protein that protects cancer from degradation.

Ute Moll. Photo courtesy of SBU

Ute Moll, professor and the vice chair for research in the Department of Pathology at the Stony Brook University School of Medicine, has made important strides in studying the effect of mutations in this gene over the last five years, demonstrating how the altered gene and the protein it creates are an important ally for cancer.

Moll published her most recent finding in this arena in the journal Cancer Cell. The Stony Brook scientist, working with an international team of researchers that included collaborators from her satellite lab at the University of Göttingen, advanced the work on previous results.

This research, which is done on mice that develop tumors through a process that more closely resembles human cancer growth, is a “very good mimic in the molecular and clinical features of human colon cancer,” Moll said.

The main research was done on a faithful mouse model of human colorectal cancer that produces mutant p53, Moll explained. She then confirmed key findings in human colon cancer cells and in survival analysis of patients.

This model allowed Moll to “study tumors in their natural environment in the intact organism with its tumor surrounding connective tissue and immune system,” Ken Shroyer, the chairman of the Department of Pathology at SBU School of Medicine, explained in an email.

The tumors that develop in these mice are driven by mutant p53 and are dependent on it for their continued growth. “These tumors overexpress mutant p53 at high levels,” which makes them a “formidable drug target for their removal,” Moll said.

By deleting the mutant p53 gene, she was able to slow and even stop the progression of the cancer. “We can show that when we remove mutant p53 either genetically or pharmacologically, we are cutting down invasiveness.” Mice with deleted mutants had fewer and smaller tumors and showed over a 50 percent reduction in invasive tumor numbers, she explained.

Finding ways to mitigate the effect of mutant p53 is important for a wide range of cancers. The mutated version Moll studied is the single most common p53 mutation in human cancer, which has a mutation that switches an amino acid for an incorrect one. This amino acid change destroys the normal function of the p53 gene.

The mutation she studies represents about 4.5 percent of all cancers. That amounts to 66,000 cancer patients in the United States each year.

More broadly, mutations in p53 in general, including those Moll didn’t study, are involved in half of all human cancers, Shroyer explained, which makes it the “single most common cancer mutation.”

Yusuf Hannun, director of the Stony Brook University Cancer Center, suggested that the work Moll did could have important clinical implications.“The deciphering of this mechanism clearly indicates new cancer therapy possibilities,” Hannun wrote in an email. The models she worked with are “quite promising.”

In addition to finding ways to stop the progression of cancer in mice with this damaged gene, Moll and her colleagues also used an Hsp90 inhibitor, which blocks a protein that protects the mutant protein from being degraded.

Inhibiting this protein has other positive effects, as the inhibitor eliminates other co-mutant proteins that could also drive tumors. “We are hitting multiple birds with one stone,” Moll said.

Hsp90 inhibitors are a “complicated story” in part because they have strong side effects in the liver and the retina. Researchers are working on the next generation of inhibitors.

A class of anti-cholesterol drugs called statins, which Moll called “one of the blockbuster drugs of medicine,” also has mutant p53 degrading effects, which work against some mutants, but not in others. The benefits are inconsistent and involve confounding variables, which makes interpreting their usefulness difficult, she added.

Moll said her recent article in Cancer Cell has triggered a number of email exchanges with a range of people, including with a patient whose cancer involved a different type of mutation. She has also had discussions with researchers on several other possible collaborations and has started one after she published her recent work.

The scientist is hopeful that her studies will continue to contribute to an understanding of the development and potential treatment of cancer.

Degrading mutant p53 has shown positive results for mice, which indicates “in principle” that such an approach could work down the road in humans, she suggested.

Ute Moll in her lab at Stony Brook University. Photo by John Griffin

Some day, people may be able to breathe easier because of a cancer researcher.

No, Ute Moll doesn’t work on respiration; and, no, she doesn’t study the lungs. What Moll, research scientist Alice Nemajerova and several other collaborators did recently, however, was explain the role of an important gene, called p73, in the formation of multiciliated cells that remove pollutants like dust from the lungs.

Initially, scientists had studied a knockout mouse, which lacked the p73 gene, to see if the loss of this gene would cause mice to develop cancers, the way they did for p73’s well-studied cousin p53. Researchers were surprised that those mice without p73 didn’t get cancer, but found other problems in the development of their brains, which included abnormalities in the hippocampus.

While each of these mice had a respiratory problem, researchers originally suspected the breathing difficulties came from an immune response, said Moll, the vice chair for experimental pathology and professor of pathology at Stony Brook University.

A board-certified anatomical and clinical pathologist who does autopsies and trains residents at Stony Brook, Moll took a closer look and saw an important difference between these mice and the so-called wild type, which has an intact p73 gene.

Moll on a recent trip to Africa says hello to Sylvester the cheetah who is the animal ambassador in Zimbabwe. Photo from Moll
Moll on a recent trip to Africa says hello to Sylvester the cheetah who is the animal ambassador in Zimbabwe. Photo from Moll

“Microscopic examinations of many types clearly showed that the multiciliated cells in the airways were severely defective,” she explained. “Instead of a lawn of dense long broom-like motile cilia on their cell surface which created a strong directional fluid flow across the windpipe surface, the [knockout] cells had far fewer cilia, and the few cilia present were mostly short stumps that lost 100 percent of their clearance function.”

This finding, which was published in the journal Genes & Development, could have implications for lung diseases such as chronic obstructive pulmonary disease, or COPD, which affects more than 330 million people around the world and is the third leading cause of death.

The discovery provides “the long-awaited explanation for the diverse phenotypes of the p73 knockout mice,” wrote Elsa Flores, a professor of molecular oncology at the UT MD Anderson Cancer Center, in a commentary of the work.

In an email, Flores said Moll is a “wonderful collaborator and colleague” whose “meticulous” work is “held in high regard.”

Carol Prives, Da Costa professor in biological sciences at Columbia University, suggested this was a “very significant finding.”

Moll and her scientific team went beyond showing that the loss of the p73 gene caused the defective or missing cilia. They took stem cells from the trachea, which can grow on a culture dish into a range of other cells. With the proper nutrients and signals, these stem cells can grow back into a fully differentiated respiratory epithelium.

The organotypic culture had the same defects as the knockout mice. The scientists then used a lentivirus to insert a copy of the functioning p73 gene. The cells in the culture developed a complete set of long, motile cilia.

“It’s a complete rescue experiment,” Moll said. “This closes the circle of proof that” p73 is responsible for the development of these structures that clean the lungs.

In addition to the lungs, mammals also develop these cilia in two other areas, in the brain and in the fallopian tubes.

There could be a range of p73 deficiencies and some of these could be indicative of vulnerability or susceptibility to lung-related problems that are connected to incomplete cilia. This could be particularly valuable to know in more polluted environments, where the concentration of dust or pollutants is high.

Moll plans to “find tissue banks from COPD patients” in which she might identify candidate alleles, or genes, that have a partial loss of function that would contribute to the reduction in the cilia cells.

While Moll will continue to work on respiration and p73 in mice, she described her broader research goals as “gene-centric,” in which she studies the entire p53 family, which includes p53, p63 and p73.

Colleagues suggested that she has made important and unexpected discoveries with p53.

“She was among the first to show that in some pathological states, p53 is sequestered in the cytoplasm rather than in the nucleus,” Prives, who has known Moll for 25 years, explained in an email. “This led to her original and very unexpected discovery that p53 associates with mitochondria and plays a direct role in mitochondrial cell death. She was very courageous in that regard since the common view was that p53 works only in the nucleus.”

Moll was raised in Germany and earned her undergraduate and medical degrees in Ulm, the same town where Albert Einstein grew up. She lives in Setauket with her husband, Martin Rocek, a professor of theoretical physics at SBU. The couple has two sons, 26-year-old Thomas, who is involved in reforestation in Peru, and 29-year-old Julian, a documentary filmmaker focusing on environmental themes.

Moll is also focused on the environment.“If humankind doesn’t wake up soon, we are going to saw off the branch we’re sitting on,” she warns. One of Moll’s pet peeves is car idling. She walks up to the windows of people sitting in idling cars and asks if they could turn off the engine.

As for her work with p73, she feels as if she is “just at the beginning. This is a rich field.”

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