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Yusuf Hannun

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.

Maurizio Del Poeta. File photo from SBU

By Daniel Dunaief

Sometimes, fixing one problem creates another.

People with multiple sclerosis have been taking a medication called fingolimod for a few years. The medicine calms immune systems that attack the myelin around nerve cells. Fingolimid decreases the lymphocyte number in the bloodstream by trapping them in the lymph nodes.

In a few cases, however, the drug can reduce the immune system enough that it allows opportunistic infections to develop. Cryptococcosis, which is a fungal infection often spread through the inhalation of bird droppings or from specific trees such as eucalyptus, is one of these infections, and it can be fatal if it’s not caught or treated properly, especially for people who have weakened immune systems.

Swiss pharmaceutical giant Novartis contacted Stony Brook University fungal expert Maurizio Del Poeta, a professor in the Department of Molecular Genetics & Microbiology, to understand how this drug opens the door to this opportunistic and problematic infection. He is also exploring other forms of this drug to determine if tweaking it can allow the benefits without opening the door to problematic infections.

Most of the human population has been exposed to this fungus. In a study in the Bronx, over 75 percent of children older than 2 years of age had developed an antibody against Cryptococcus neoformans, which means they have been exposed to it. It is unknown whether these people harbor the fungus or if they have just mounted an immune reaction. Exposure may be continuous, but infections may only occur if a person is immunocompromised.

Fingolimid “inhibits a type of immunity” that involves the movement of lymphocytes from organs into the bloodstream,” Del Poeta said. “Because of this, there are certain infections that can develop.”

Through a spokeswoman, Novartis explained that the company was “happy to have started a scientific collaboration” with Del Poeta to understand the role of a specific pathway in cryptococcus infections.

Cryptococcal meningitis is one of several infections that can develop. Others include herpes meningitis and disseminated varicella zoster. Before starting fingolimid, patients need to receive immunization for varicella zoster virus. At this point, doctors do not have a vaccine for cryptococcosis.

To study the way this drug and its derivatives work, Del Poeta recently received a $2.5 million grant over a five-year period from the National Institutes of Health.

Yusuf Hannun, the director of the Cancer Center at SBU, was confident Del Poeta would continue to be successful in his ongoing research.

Del Poeta “does very important and innovative work on fungal pathogenesis and he is a leader in the field,” Hannun wrote in an email. “His work will enhance our understanding of the molecular mechanisms.”

Fingolimid mimics a natural lipid. Years ago, Del Poeta showed that this sphingolipid, which is on the external surface of the membrane, is important to contain cryptococcosis in the lung. If its level decreases, the fungus can move from the lung to the brain.

While people with multiple sclerosis have developed signs of this infection, it is also prevalent in areas like sub-Saharan Africa, where people with AIDS battle cryptococcosis. About 40 percent of this HIV population develops this fungal infection, Del Poeta said. About 500,000 people die of cryptococcosis every year.

In certain areas of the United States, such as the Pacific Northwest, this fungus is also endemic. On Vancouver Island, about 19 people died from Cryptococcus gattii infections between 1999 and 2007. Most of those patients were immunocompromised.

When the fungus migrates from the lung to the brain, it is “very difficult, if not impossible in most cases, to eradicate,” Del Poeta explained in an email. If the diagnosis is made early enough before the infection spreads to the brain, the recovery rate is high, he suggested. In people whose immune systems are not compromised by drugs or disease, “death is rare.” 

Del Poeta plans to study the interaction between the drug and the fungal infection through a mouse model of the disease. The mouse model mimics the human disease and will provide insights on how to control the infection, particularly when the fungus reaches the brain.

Some of the derivatives Novartis has developed do not cause a fungal infection. Del Poeta is working with Novartis to study other forms of fingolimid that do not reactivate cryptococcosis. Del Poeta said Novartis is currently in Phase III clinical trials for another drug for multiple sclerosis. The new drug acts on a different receptor.

“We think the reason the fingolimid reactivates cryptococcosis is that it is blocking one receptor, which is important for the containment” of the fungus. The other drug doesn’t allow the disease-bearing agent to escape.

“This is a hypothesis,” Del Poeta said. He is waiting to corroborate the cell culture data in animal models.

Del Poeta has been working with Novartis for over three years. The Stony Brook scientist used some preliminary studies on the way fingolimid analogs behave as part of the research grant application to the NIH that led to the current grant.

Del Poeta said he is excited about the possibility of contributing to this area.

“Not only will this work contribute to the field of MS, but it will also have a contribution to the field of cryptococcosis,” he said. “This will have important implications for MS patients [and] for the entire HIV population.” He said he believes patients may have some other defect. If he is able to discover what that is, he may be able to protect them from a cryptococcosis infection.

Ultimately, Del Poeta hopes this work leads to a broader understanding of fungal infections that could apply to other pathogens as well.

Mycobacterium tuberculosis causes a granuloma very similar to the one caused by the cryptococcosis and we could potentially study whether the same molecular mechanisms involved in the control of the infection in the lung are similar between the two infections,” he explained in an email.

Michael Airola. Photo from SBU

By Daniel Dunaief

Numerous trucks arrive at a construction site, each doing their part to make a blueprint for a building into a reality. In a destructive way, molecules also come together in cancer to change cells that cause damage and can ultimately kill.

Researchers often know the participants in the cancer process, although the structure of each molecule can be a mystery. Determining how the parts of an enzyme work could allow scientists and, eventually, doctors to slow those cancer players down or inactivate them, stopping their cell-damaging or destroying processes.

Recently, Michael Airola, who started his own lab at Stony Brook University early this year and is an assistant professor of biochemistry and cell biology, published a paper in the Proceedings of the National Academy of Sciences in which he showed the structure of an important enzyme that contributes to cell growth regulation in cancer and other diseases, including Alzheimer’s disease.

Called neutral sphingomyelinase, this enzyme produces ceramide, which allows cancer cells to become metastatic. Finding the structure of an enzyme can enable scientists to figure out the way it operates, which can point to pharmacological agents that can inhibit or deactivate the enzyme.

“We are trying to understand the link between structure and function to try to get the first sort of snapshots or pictures of what these enzymes look like” in the on and off states, said Airola. In his research, he showed what this enzyme looked like in its off or inactive state.

Airola joined Stony Brook Cancer Center Director Yusuf Hannun’s lab as a postdoctoral researcher in 2010, when Hannun was working in Charleston, South Carolina, at the Medical University of South Carolina. When Hannun moved to SBU in March of 2012, Airola joined him, continuing his postdoctoral research.

Michael Airola in April in New Orleans aboard the steamboat Natchez on the Mississippi River with his family, wife Krystal Airola, four-year-old Harper and two-year-old Grady. Photo from Michael Airola

Airola conducted his research at Stony Brook and Brookhaven National Laboratory, where he used a technique called X-ray crystallography, which shows the structure of crystallized molecules. Getting this enzyme to crystallize took considerable effort, especially because it has what Airola described as a floppy segment between two rigid structures.

Those floppy pieces, which Airola said aren’t the active sites of the enzyme, can interfere with the structural analysis. To see the important regions, Airola had to cut those flexible parts out, while fusing the rest of the enzyme into a single structure.

The crystallization took almost three years and was a “very difficult process,” Airola recounted. “To get proteins to crystallize, you need to get them to pack together in an ordered fashion.” He said he needed to develop some biochemical tricks to delete a large part in the middle of the protein. “Once we found the right trick and the right region to delete, we were able to crystallize the protein in about three months.”

Airola said he took considerable care to make sure removing the floppy or flexible region didn’t disrupt the function of the enzyme. Hannun and Airola are co-mentoring Prajna Shanbhogue, a graduate student who is in the process of discovering molecules that activate and inhibit the enzyme.

Hannun was pleased with the work Airola did in his lab, which he suggested was a “challenging type of research. Getting to a structure of a protein or enzyme (a specific type of protein) can take several years and is never guaranteed of success, but the rewards can be tremendous,” Hannun explained in an email, adding that Airola was a “critical contributor” and introduced structural biology to his group.

While Airola will continue to work on this enzyme, he is exploring another enzyme, in a collaboration with Hannun and John Haley at Stony Brook, that is involved in colon cancer.

Airola, two graduate students and three undergraduates in his lab are focusing considerable energy on an enzyme involved in the production of triglycerides.

Airola recently received a three-year, $231,000 grant from the American Heart Association to study lipins, a class of enzyme that plays a role both in heart disease and in diabetes. As he did with the enzyme that makes ceramide, Airola is developing a way to understand the structure and function of the triglyceride enzyme. He’d like to find out how this enzyme is regulated. “We’re trying to see if we can inhibit that enzyme, too,” he said.

Airola has “some creative ideas about using information from lipin proteins in plants and fungi, which have a less complex protein structure than mammalian lipins but catalyze the same biochemical reaction,” Karen Reue, a professor in the Department of Human Genetics, David Geffen School of Medicine at UCLA and a collaborator with Airola, explained in an email.

Reue’s lab will complement Airola’s work by conducting physiological analyses of the various “minimal” lipin proteins in processes that the mammalian proteins perform, including triglyceride biosynthesis.

While lipin proteins are necessary for metabolic homeostasis, Reue said a reasonable but still challenging goal might be to modulate the enzyme’s activity for partial inhibition in areas such as adipose tissue, while allowing the triglycerides to perform other important tasks.

Airola lives in East Setauket with his wife Krystal Airola, who is doing her residency in radiology at SBU, and their two children, four-year-old Harper and two-year-old Grady. The couple, who is expecting a third child next month, enjoy living in East Setauket, where they appreciate that they have a forest in their backyard and they can enjoy the water in Port Jefferson and West Meadow Beach.

When Airola’s postdoctoral position ended, he did a broad, national search for his next position and was delighted that he could remain at Stony Brook. “We love the area,” he said. “The research and science here are fantastic.” Airola’s collaborators are optimistic about the prospects for his research.

He is an “up and coming structural biologist that has already made important contributions to the field of lipid biology” Reue said and is a “creative and rigorous scientist with a bright future.”

Photo from Stony Brook Medicine

By Samuel L. Stanley, Jr.

Samuel L. Stanley Jr.

In recognition of his dedication to the cancer fight, Stony Brook University proudly honored the 47th Vice President of the United States Joseph R. Biden Jr. at the Stars of Stony Brook Gala — our annual fundraising event — on Wednesday, April 19.

Hosted by the Stony Brook Foundation, the gala generates funds for student financial aid and a select academic area of excellence. This year, the university raised $6,946,000 in gifts and pledges, including $2,051,000 for scholarships and $4,895,000 to support the Stony Brook University Cancer Center. Since 2000, the event has raised more than $50 million.

As vice president, Joe Biden led the White House Cancer Moonshot Task Force. Its mission: to double the rate of progress in preventing the disease that leads to more than 8 million deaths worldwide every year. The intention, said Biden in his remarks, was to infuse the cancer research culture with “the urgency of now.”

At Stony Brook, we share Joe Biden’s determination, sense of urgency and his fundamental confidence in our ability to make a difference in the fight against cancer. The Stony Brook Cancer Center brings together the brightest minds, enhancing purposeful collaboration, and creating strategic partnerships to share information and accelerate research.

Our researchers are receiving worldwide attention for a pioneering study of the genesis and behavior of cancer cells at the molecular level with the goal of one day helping to detect, treat and eventually eliminate the disease for good.

Through continual research and discovery, Stony Brook Cancer Center is on the forefront of cancer care. In the new Kavita and Lalit Bahl Center for Metabolomics and Imaging, for instance, Dr. Yusuf Hannun and Dr. Lina Obeid are receiving international recognition for their pioneering studies in the relationship between cancer and lipids, naturally occurring molecules in the body such as fats. Their work is changing what is known about the role lipids play in cancer and brings us closer to understanding how to prevent and treat the disease.

Next year, the Stony Brook Cancer Center will relocate from its current location on the Stony Brook Medicine campus to the new 254,000-square-foot Medical and Research Translation (MART) building, designed to enable scientists and physicians to work side by side to advance cancer research and imaging diagnostics.

We’re thrilled that for one big night, we shined a white-hot light on the cancer issue and worked to raise awareness and money that will no doubt play a continuing role in bringing an end to this disease.

Dr. Samuel L. Stanley Jr. is president of Stony Brook University.

Escobar-Hoyos, center, holds her recent award, with Kenneth Shroyer, the chairman of the Department of Pathology at Stony Brook on the left and Steven Leach, the director of the David M. Rubenstein Center for Pancreatic Cancer Research on the right. Photo by Cindy Leiton

By Daniel Dunaief

While winter storm Niko in February closed schools and businesses and brought considerable precipitation to the region, it also coincided with great news for Luisa Escobar-Hoyos, who earned her doctorate from Stony Brook University.

Escobar-Hoyos, who is a part-time research assistant professor in the Department of Pathology at Stony Brook University and a postdoctoral fellow at Memorial Sloan Kettering Cancer Center, received word that she was the sole researcher selected in the country to receive the prestigious $600,000 Pancreatic Cancer Action Network–American Association for Cancer Research Pathway to Leadership Award.

When she heard the news, Escobar-Hoyos said she was “filled with excitement.” After she spoke with her husband Nicolas Hernandez and her current mentor at MSKCC, Steven Leach, the director of the David M. Rubenstein Center for Pancreatic Cancer Research, she called her parents in her native Colombia.

Her mother, Luz Hoyos, understood her excitement not only as a parent but as a cancer researcher herself. “My interest in cancer research started because of my mom,” Escobar-Hoyos said. Observing her example and “the excitement and the impact she has on her students and young scientists working with her, I could see myself” following in her footsteps.

The researcher said her joy at winning the award has blended with “a sense of responsibility” to the growing community of patients and their families who have developed a deadly disease that is projected to become the second leading cause of cancer-related death by 2020, according to the Pancreatic Cancer Action Network, moving past colorectal cancer.

The Pancreatic Cancer Action Network has awarded $35 million in funding to 142 scientists across the country from 2003 to 2016, many of whom have continued to improve an understanding of this insidious form of cancer.

David Tuveson, the current director of the Cancer Center at Cold Spring Harbor Laboratory, received funds from PanCan to develop the first genetically engineered mouse model that mimics human disease. Jiyoung Ahn, the associate director of the NYU Cancer Institute, used the funds to discover that two species of oral bacteria are associated with an over 50 percent increased risk of pancreatic cancer.

Over the first decade since PanCan started awarding these grants, the recipients have been able to convert each dollar granted into $8.28 in further pancreatic cancer research funding.

In her research, Escobar-Hoyos suggests that alternative splicing, or splitting up messenger RNA at different locations to create different versions of the same protein, plays an important part in the start and progress of pancreatic cancer. “Her preliminary data suggest that alternative splicing could be associated with poorer survival and resistance to treatment,” Lynn Matrisian, the chief science officer at PanCan, explained in an email. “The completion of her project will enhance our understanding of this molecular modification and how it impacts pancreatic cancer cell growth, survival and the progression to more advanced stages of this disease.”

Escobar-Hoyos explained that she will evaluate how mutations in transcriptional regulators and mRNA splicing factors influence gene expression and alternative splicing of mRNAs to promote the disease and aggression of the most common form of pancreatic cancer. Later, she will evaluate how splicing regulators and alternatively spliced genes enriched in pancreatic ductal adenocarcinoma contribute to tumor maintenance and resistance to therapy.

Escobar-Hoyos will receive $75,000 in each of the first two years of the award to pay for a salary or a technician, during a mentored phase of the award. After those two years, she will receive $150,000 for three years, when PanCan expects her to be in an independent research position.

Escobar-Hoyos said her graduate research at Stony Brook focused on ways to understand the biological differences between patients diagnosed with the same cancer type. She helped discover the way a keratin protein called K17 entered the nucleus and brought another protein into the cytoplasm, making one type of tumor more aggressive.

While Escobar-Hoyos works full time at Memorial Sloan Kettering, she continues to play an active role in Kenneth Shroyer’s lab, where she conducted experiments for her doctorate. She is the co-director of the Pathology Translational Research Laboratory, leading studies that are focused on pancreatic cancer biomarkers. The chair in the Department of Pathology, Shroyer extended an offer for her to continue to address the research questions her work addressed after she started her postdoctoral fellowship.

“When you do research projects and you develop them from the beginning, they are like babies and you really want to see how they evolve,” Escobar-Hoyos said. Numerous projects are devoted to different aspects of K17, she said.

Shroyer said Escobar-Hoyos had already been the first author on two landmark studies related to the discovery and validation of K17 even before her work with pancreatic cancer. “She has also conducted highly significant new research” that she is currently developing “that I believe will transform the field of pancreatic cancer research,” Shroyer wrote in an email.

Shroyer hopes to recruit Escobar-Hoyos to return to Stony Brook when she completes her fellowship to a full-time position as a tenure track assistant professor. “Based on her achievements in basic research and her passion to translate her findings to improve the care of patients with pancreatic cancer, I have no doubt she is one of the most promising young pancreatic cancer research scientists of her generation,” he continued.

Yusuf Hannun, the director of the Stony Brook Cancer Center, said Escobar-Hoyos’s work provided a new and important angle with considerable promise in understanding pancreatic cancer. “She is a tremendous example of success for junior investigators,” Hannun wrote in an email.

Escobar-Hoyos said she is hoping, a year or two from now, to transition to becoming an independent scientist and principal investigator, ideally at an academic institution. “Because of my strong ties with Stony Brook and all the effort the institution is investing in pancreatic research” SBU is currently her first choice.

Escobar-Hoyos is pleased that she was able to give back to the Pancreatic Cancer Action Network when she and a team of other friends and family helped raise about $4,000 as a part of a PurpleStride 5K walk in Prospect Park earlier this month.“I was paying forward what this foundation has done for me in my career,” she said.

Matrisian said dedicated scientists offer hope to patients and their families. “Researchers like Escobar-Hoyos spark scientific breakthroughs that may create treatments and ultimately, improve the lives of patients,” she suggested.

At the ribbon cutting of the Kavita and Lalit Bahl Center for Metabolomics and Imaging last December, from left, Lina Obeid; Yusuf Hannun; Kavita and Lalit Bahl; Samuel Stanley, President of Stony Brook University; and Kenneth Kaushansky, dean of Stony Brook University’s School of Medicine. Photo from SBU

By Daniel Dunaief

Many ways to kill cancer involve tapping into a cell’s own termination system. With several cancers, however, the treatment only works until it becomes resistant to the therapy, bringing back a life-threatening disease.

Collaborating with researchers at several other institutions, Dr. Lina Obeid, the director of research at Stony Brook University School of Medicine, has uncovered a way that cancer hides a cell-destroying lipid called ceramide from treatments. The ceramide “gets co-opted by fatty acids for a different species of fats, namely acylceramide, and gets stored side by side with the usual triglycerides,” Obeid explained in an email about her recent finding, which was published in the journal Cell Metabolism. “It makes the ceramide inaccessible and hence the novelty.” The ceramide gets stored as a lipid drop in the cell.

“We describe a completely new metabolic pathway and role in cell biology,” Obeid said. Other researchers suggested that this finding could be important in the battle against cancer. “That acylceramides are formed and deposited in lipid droplets is an amazing finding,” George Carman, the director of the Rutgers Center for Lipid Research, explained in an email. “By modifying the ceramide molecule with an acyl group for its deposit in a lipid droplet takes ceramide out of action and, thus, ineffective as an agent to cause death of cancer cells.”

Carman said Obeid, whom he has known for several years, visited his campus in New Jersey to share her results. “All of us at Rutgers were so excited to hear her story because we knew how important this discovery is to the field of lipid droplet biology as well as to cancer biology,” he said. Obeid conducted some of the work at the Kavita and Lalit Bahl Center for Metabolomics and Imaging at Stony Brook University. The center officially opened on Dec. 1 of last year on the 15th floor of the Health Sciences Center and will move to the Medical and Research Translation Building when it is completed next year. “This study is exactly the kind of major questions we are addressing in the center that [the Bahls] have generously made possible,” she explained.

Obeid discovered three proteins that are involved in this metabolic pathway: a ceramide synthesizing protein called CerS, a fatty acyl-CoA synthetase protein called ACSL and an enzyme that puts them together, called DGAT2, which is also used in fatty triglyceride synthesis. Her research team, which includes scientists from Columbia University, Northrop Veterans Affairs Medical Center and Mansoura University in Egypt is looking into implications for the role of this novel pathway as a target for cancer and obesity.

Indeed, obesity enables more frequent conversion of ceramide into acylceramide. “Fats in cells and in diets increase and predispose to obesity,” Obeid suggested. “This new pathway we found occurs when fatty acids are fed to cells or as high-fat diets are fed to mice.” In theory, this could explain why obesity may predispose people to cancer or make cancer resistance more prevalent for some people. According to Obeid, a high-fat diet can cause this collection of proteins to form in the liver of mice, and she would like to explore the same pathways in humans. Before she can begin any such studies, however, she would need numerous approvals from institutional review boards, among others.

Obeid and her collaborators hypothesize that a lower-fat diet could reduce the likelihood that this lipid would be able to evade cancer therapies.

These kinds of studies “provide the justification for looking at the effect of diet on acylceramide production,” Daniel Raben, a professor of biological chemistry at Johns Hopkins University School of Medicine, explained in an email. Further research could include “isocaloric studies with [high-fat diets] and [low-fat diets] in animals that are age and gender matched.”

Obeid was a part of the first group to describe the lipid’s role in cancer cell death in 1993. “We have been studying its metabolism and looking at how it’s made and broken down,” she said. “We found recently that it associates with these proteins to metabolize it.”

While the lipid provides a way to tackle cancer’s resistance to chemotherapy, it also has other functions in cells, including as a membrane permeability barrier and in skin. A therapy that reduced acylceramide could affect these other areas but “as with hair loss [with chemotherapy treatment], this will likely be easily managed and reversible,” Raben explained.

Obeid and Yusuf Hannun, the director of the Cancer Center at Stony Brook, are searching for other scientists to work at the Kavita and Lalit Bahl Center for Metabolomics and Imaging. “We are actively recruiting for star scientists” at the center, Obeid said. Other researchers suggested that the history of the work Obeid and Hannun have done will attract other researchers.

Hannun and Obeid are “considered the absolute leaders in the area of sphingolipid biochemistry and their clinical implications,” Raben said. “Simply put, they are at the top of this academic pile. Not only are they terrific scientists, they also have an outstanding and well-recognized reputation for training and nurturing young investigators.” Carman asked, “Who wouldn’t want to be associated with a group that continues to make seminal contributions to cancer biology and make an impact on the lives of so many?”

As for the next steps in this particular effort, Carman foresaw some ways to extend this work into the clinical arena. “I can imagine the discovery of a drug that might be used to combat cancer growth,” Carman said. “I can imagine the discovery of a drug that might control the acylation of ceramide to make ceramide more available as a cancer cell inhibitor. Clearly, [Obeid’s] group, along with the outstanding colleagues and facilities at Stony Brook, are positioned to make such discoveries.”

David Matus in his lab at Stony Brook University. Photo courtesy of SBU

By Daniel Dunaief

At first look, the connection between a roundworm, a zebrafish and cancer appears distant. After all, what can a transparent worm or a tropical fish native to India and the surrounding areas reveal about a disease that ravages its victims and devastates their families each year?

Plenty, when talking to David Matus and Benjamin Martin, assistant professors in the Department of Biochemistry and Cell Biology at Stony Brook University whose labs are next door to each other. The scientific tandem recently received the 2017 Damon Runyon–Rachleff Innovation Award, which includes a two-year grant of $300,000, followed by another renewable grant of $300,000 to continue this work.

In the first of a two-part series, Times Beacon Record Newspapers will profile the work of Matus this week. Next week the Power of Three will feature Martin’s research on zebrafish.

Long ago a scientist studying dolphin cognition in Hawaii, Matus has since delved into the world of genetic development, studying the roundworm, or, as its known by its scientific name, Caenorhabditis elegans. An adult of this worm, which lives in temperate soil environments, measures about 1 millimeter, which means it would take about 70 of them lined up end to end to equal the length of an average earthworm.

From left, David Matus and Benjamin Martin. Photo courtesy of SBU

Matus specifically is interested in exploring how a cell called the anchor cell in a roundworm invades through the basement membrane, initiating a uterine-vulval connection that allows adult roundworms to pass eggs to the outside environment. He is searching for the signals and genetic changes that give the anchor cell its invasive properties.

Indeed, it was through a serendipitous discovery that he observed that the loss of a single gene results in anchor cells that divide but don’t invade. These dividing cells are still anchor cells, but they have lost the capacity to breach the basement membrane. That, Matus said, has led the team to explore the ways cancer has to decide whether to become metastatic and invade other cells or proliferate, producing more copies of itself. In some cancers, their hypothesis suggests, the cells either divide or invade and can’t do both at the same time. It could be a cancer multitasking bottleneck.

Mark Martindale, the director of the Whitney Laboratory at the University of Florida in Gainesville who was Matus’ doctoral advisor, said a cell’s decision about when to attach to other cells and when to let go involves cell polarity, the energetics of motility and a host of other factors that are impossible to study in a mammal.

The roundworm presents a system “in which it is possible to manipulate gene expression, and their clear optical properties make them ideal for imaging living cell behavior,” Martindale explained in an email. Seeing these developmental steps allows one to “understand a variety of biomedical issues.”

Last year, Matus and Martin were finalists for the Runyon–Rachleff prize. In between almost getting the award and this year, the team conducted imaging experiments in collaboration with Eric Betzig, a group leader at the Janelia Research Campus of the Howard Hughes Medical Institute in Ashburn, Virginia. Betzig not only brings expertise in optical imaging technologies but also has won a Nobel Prize.

“We really appreciate the opportunity to work with [Betzig] and his lab members on this project,” said Matus, who also published a review paper in Trends in Cell Biology that explored the link between cell cycle regulation and invasion. He and his graduate student Abraham Kohrman explored the literature to find cases that showed the same switching that he has been exploring with the roundworm.

Yusuf Hannun, the director of the Stony Brook Cancer Center, said the work is highly relevant to cancer as it explores fundamental issues about how cells behave when they invade, which is a key property of cancer cells. Hannun said the tandem’s hypothesis about division and invasion is “consistent with previous understandings but I believe this is the first time it is proposed formally,” he suggested in an email.

Their work could apply to invasive epithelial cancers, suggested Scott Powers, a professor in the Department of Pathology at Stony Brook and the director of Clinical Cancer Genomics at the Cancer Center. That could include breast, colon, prostate, lung and pancreatic cancers, noted Powers, who is a recent collaborator with Matus and Martin.

The additional funding allows Matus and Martin to focus more of their time on their research and less on applying for other grants, Matus said.

Back row from left, David Matus and his father in law Doug Killebrew; front row from left, Maile 9, Bria, 7, and Matus’ wife Deirdre Killebrew. Photo by Richard Row

Matus lives in East Setauket with his wife Deirdre Killebrew, who works for Applied DNA Sciences. The couple met when they were working with dolphins in Hawaii. Matus’ first paper was on dolphin cognition, although he switched to evolutionary and developmental biology when he worked in Martindale’s lab at the University of Hawaii.

Martindale described Matus as prolific during his time in his lab, publishing numerous papers that were “profoundly important in our continued understanding of the relationship between genotype and phenotype and the evolution of biological complexity,” Martindale wrote in an email.

Following in Martindale’s footsteps, Matus replaced his middle name, Samuel, in publications with a Q. Martindale said several of his colleagues adopted the phony Q to pay homage to the attitude that drove them to pursue careers in science. Matus has now passed that Q on to Korhman, who is his first graduate student.

Matus and Killibrew have two daughters, Bria and Maille, who are 7 and 9 years old. Their children have a last name that combines each of their surnames, Matubrew. Matus said he feels “fortunate when I got here three years ago that they had me set up my lab next to [Martin]. That gave us an instantaneous atmosphere for collaboration.”

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