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PHILADELPHIA — (Oct. 2, 2025) — Wistar Institute researchers have overturned three decades of scientific thinking about p53, the most important tumor suppressor protein in cancer research. In a study published in Molecular Cell, they reveal for the first time that this critical protein, responsible for halting cell division or initiating cell death, changes its binding sites according to specific cellular signals. The findings challenge the long-held scientific belief that p53 always activated the same set of genes regardless of cellular context or outcome. Instead, researchers discovered that p53 can be directed by the enzyme PADI4 to leave some of its usual binding sites and relocate to genes that generate an immune response to attack tumors.

“For 30 years, we joked that p53 was ‘dumb’ because it couldn’t decide what to do in different situations—it just turned on all its target genes whether the cell needed to die or survive, and the cell decided which activity needed to happen,” said Maureen Murphy, Ph.D., Deputy Director of the Ellen and Ronald Caplan Cancer Center, Ira Brind Professor & Program Leader of the Molecular and Cellular Oncogenesis Program at The Wistar Institute, and senior author of the study.

“This is the first example of p53 actually reading a signal and deciding where on DNA to bind. It’s a completely different mechanism that shows p53 is actually quite smart and, as I suspected, engages the immune system in order to suppress cancer.”

The discovery emerged from Murphy’s decades-long investigation into genetic variants found in families of African descent who develop cancer at accelerated rates but don’t fit typical hereditary cancer patterns. These families carry partially functional versions of p53—called hypomorphic variants—which are understudied and therefore leave patients without clear medical guidance. Murphy and her team hypothesized that studying these semi-functional variants that are associated with cancer, would reveal the key target gene for p53 tumor suppression.

By comparing the function of six p53 hypomorphs to the “normal” or wild-type version of p53, the team identified PADI4 as the only p53 target gene that would typically be activated by wild-type p53 but remained inactive across all six of the hypomorphic variants they tested. They also found that PADI4 doesn’t just respond to commands from p53—it actually directs p53’s behavior through a process called citrullination. When PADI4 citrullinates p53 (adding chemical tags to specific amino acid residues), it fundamentally changes where p53 goes in the cell’s DNA. Instead of binding to its usual genes, the modified p53 relocates to genes associated with ETS transcription factors, which are known to regulate immune response genes. This gives scientists a whole new perspective on p53’s role in responding to cancer.

“P53’s real tumor suppressive role appears to be to alert the immune system to come and eradicate the tumor,” said Murphy.”

The researchers demonstrated this mechanism using advanced genomic techniques, showing that when PADI4 is active, p53 abandons about 30% of its normal binding sites while moving to new locations that activate genes responsible for the interferon response—the cell’s primary antiviral and anti-tumor defense system. To do this, Murphy and her team developed new antibodies specific to citrullinated p53 and used cutting-edge techniques including ChIP-seq and CUT&Tag to map precisely where the modified p53 binds in living cells. They confirmed this mechanism in multiple cell lines and validated it in mouse models.

This discovery has important implications for cancer treatment and diagnosis. Since certain hypomorphic p53 variants cannot properly activate PADI4, these patients may not respond as well to immunotherapies that rely on the body’s natural immune response to fight cancer. Therefore, Murphy suggests, PADI4 could serve as a potential biomarker to help clinicians guide treatment decisions.

“We might be able to predict whether someone will respond to immunotherapy based on their p53 status and PADI4 function. Instead of trying immunotherapy and finding out it doesn’t work, we could direct treatment more precisely from the start. In fact, one of our areas of focus is to identify personalized therapies for people with hypomorphic p53 variants.”

Importantly, this discovery represents more than just a scientific advance. It validates Murphy’s long-held conviction that studying historically underrepresented populations can lead to breakthrough insights. Some families of African descent have the highest cancer burden of any ethnic group, yet their genetic variants have been largely understudied.

“These families are getting cancer in their 30s and 40s, and genetic counselors are telling them ‘sorry, we don’t know if this mutation is really responsible for increasing your cancer risk,’” Murphy said of African descent families with hypomorphic p53 variants.

“By studying people who are marginalized and variants that were being ignored, we ended up discovering a fundamental new mechanism of how the most important tumor suppressor actually works.”

Co-authors: Alexandra Indeglia, Andrea Valdespino, Giulia Pantella, Sarah Offley, Connor Hill, Maya Foster, Kaitlyn Casey, HsinYao Tang, Anneliese M. Faustino, Alessandro Gardini, and Maureen E. Murphy from The Wistar Institute.

Work supported by:National Health Institutes (NIH) grants R01 CA102184 to M.E.M., F31 CA277953 to A.I., and R50 CA221838 to H.Y.T. Wistar shared resources are supported by the Cancer Center Support Grant P30 CA010815.

Publication information: Targeted Citrullination Enables p53 Binding to Non-canonical Sites, Molecular Cell, 2025. Online publication.

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PHILADELPHIA — (Sept. 9, 2025) — New research by Wistar Institute scientists shows how targeting a cleft in the retinoblastoma protein can kill tumor-protecting macrophages in ovarian cancer. The discovery provides a novel therapeutic target that could potentially make ovarian and other cancers more sensitive to immunotherapies. Their findings are published in Cancer Immunology Research, a journal of the American Association for Cancer Research.

It’s a surprising finding, since retinoblastoma protein is more often understood to suppress cancer cells; in theory, blocking it should speed up cancer growth. However, researchers found that by targeting only part of the protein, they could turn off its ability to protect tumor-supporting macrophages, without affecting its cancer-suppressing abilities.

“This is a first-in-kind target against a solid tumor, in this case ovarian cancer,” said senior author Dr. Luis Montaner, D.V.M., D.Phil., executive vice president of The Wistar Institute, and director of the HIV Cure and Viral Diseases Center. “It’s exciting, because it opens up a novel therapeutic target that has never been described before.”

Macrophages are immune cells that have different functions in the body. While some macrophages help the immune system target and fight diseases, others support wound healing by calming the immune response to protect tissues undergoing repair. Tumors like ovarian cancer use these second kind of macrophages to create a protective environment that shields them from immune attack.

Previous studies have shown that these macrophages could be targeted with drugs. However, scientists found they could not target tumor-supporting macrophages without also wiping out beneficial macrophages that fight disease.

While the new discovery has important implications for cancer treatment, it actually grew out of HIV studies, noted Montaner, a prominent HIV researcher. He said scientists had been investigating the role of macrophages in HIV infection when they discovered that retinoblastoma protein plays a key role in helping macrophages survive HIV infection. Researchers then wondered if the protein played a similar role in the survival of tumor-supporting macrophages in cancer.

In subsequent lab studies they found that blocking a specific cleft in the protein turned off this survival mechanism without disabling the protein itself. This depleted the population of tumor-protecting macrophages, leaving the tumor cells vulnerable to immune attack.

Researchers then tested this approach in animals and found that their tumors shrank.

Montaner noted that the discovery was a years-long process because the findings were so unexpected and went against established thinking about the role of retinoblastoma protein in cancer. With each new experiment, researchers expected to be proven wrong.

“As time progressed the data kept piling up, until we ended up with a large body of evidence behind one straightforward conclusion,” he said.

Altogether it took more than 10 years from the time his team first linked retinoblastoma with macrophage survival to the publication of their collective findings supporting this new approach to treat cancer.

Montaner said the study pointed to the importance of interdisciplinary research, and how discoveries in one area of medicine, like HIV, can lead to breakthrough in other fields like cancer.

“Our bodies were designed to survive in a hostile environment where you cannot predict what kind of threat you will encounter,” he said. “So whether it’s autoimmunity, cancer, or an infection, a lot of the same processes are engaged. When you learn how to manipulate or control a certain response, it is very likely it is reflected in other aspects of your engagement with disease, which is exactly what happened here.”

Next, the team is working on follow-up research, including studying how regulating retinoblastoma protein affects macrophages in acute myeloid leukemia and pancreatic cancer. They will also test the approach in combination with immunotherapy.

“We’ve learned a lot about how to manipulate this target,” he said. “We also know its therapeutic potential may not be restricted to ovarian cancer, and that there may be an opportunity to join it with other therapies that would then be more impactful.”

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PHILADELPHIA — (Sept. 4, 2025) — The Wistar Institute, an international biomedical research leader in cancer, immunology and infectious diseases, announces the appointment of Katherine Aird, Ph.D., as co-leader and professor in the Molecular and Cellular Oncogenesis Program of the Ellen and Ronald Caplan Cancer Center.

Aird’s research is in cancer metabolism and cell cycle disruption, which influence cancer cell growth and division. She focuses on how cancer cells communicate through metabolites and how this consumption of metabolites (metabolism) influences the ways cells proliferate and divide. Aird studies this process in especially aggressive cancers like melanoma and ovarian cancer to understand the hallmarks of how metabolism and crosstalk can drive cancer progression and resistance. And conversely how to therapeutically target these changes to reverse metabolism and ultimately shrink or destroy tumors.

“Katherine brings powerful expertise in tumor metabolism to the deep well of cancer biology knowledge and biomedical research excellence that is our Ellen and Ronald Caplan Cancer Center,” said Dario Altieri, M.D., president and CEO of The Wistar Institute, director of the Ellen and Ronald Caplan Cancer Center and Robert and Penny Fox Distinguished Professor.

“She returns full circle to Wistar, where she trained as a postdoctoral fellow. Now, she focuses on the next frontier of cancer cell communication together with creating a new Wistar initiative around tumor metabolism. Through her leadership, Wistar continues to strengthen its multidisciplinary science and tackle cancer through multiple lenses.”

The study of metabolism — how cancer cells rewire nutrient uptake to support unchecked cell growth — is strong at Wistar with many scientists examining it from different research vantage points.

“There is an umbrella of cancer metabolism knowledge at Wistar,” said Aird. “We have PIs specialized in metabolism from a cancer cell-intrinsic niche, focused on the tumor microenvironment; some study the microbiome — an important and completely different aspect of tumor metabolism; and some focus on where immunology and metabolism intersect. Many are metabolism-adjacent and “touching” metabolism through their research in autophagy (cellular recycling) or how changes in lipids drives cancer growth or resistance to therapies. We have many experts here with cancer biology, immunology, genetics, and virology knowledge working on this massive puzzle that is cancer metabolism. It is an incredibly exciting time to be a part of it at Wistar.”

Dr. Aird received her B.A. in biology from Johns Hopkins University followed by a Ph.D. from Duke University. In 2010, she joined the lab of Dr. Rugang Zhang at Fox Chase Cancer Center as a postdoctoral fellow and moved with him to The Wistar Institute in 2012. In 2015, she received an NCI K99/R00 Pathway to Independence Award, and in 2016 she started her independent lab at Penn State College of Medicine as an assistant professor. She moved to the University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center in 2020 as an associate professor before joining The Wistar Institute as a professor and co-leader of the Molecular and Cellular Oncogenesis Program.

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PHILADELPHIA — (Aug. 15, 2025) — The Wistar Institute, an international biomedical research leader in cancer, immunology and infectious disease, announces the appointment of Simon Chu, Ph.D., as Caspar Wistar Fellow in the Molecular and Cellular Oncogenesis Program. Chu’s research focuses on genomics data analysis, through the creation & design of novel computational programs and applied machine learning, to uncover and interpret cancer and infectious disease research and identify drug discovery potential.

“There are fundamental molecular, cellular and genetic questions our Wistar scientists are trying to understand, and Simon brings the application of deep science and machine learning algorithms to integrate with our research and solve questions that can only happen through the power of data and collaboration,” said Dario Altieri, M.D., president and CEO of The Wistar Institute, director of the Ellen and Ronald Caplan Cancer Center and the Robert and Penny Fox Distinguished Professor. “Simon’s expertise offers a rich new dimension to the core biological questions we are trying to solve.”

Chu is interested in the genome and within it transposable elements or “jumping genes” that can rearrange themselves to alter gene expression and impact function. He creates algorithms to investigate why and how these genetic changes happen and their implications in disease.

“I’m excited to join Wistar because of the different computational biology subdomains right here at the Institute,” said Chu. “This field is transformative. I focus on genomics research and understanding the data encoded within genome sequences. But there are other computational biologists here with different expertise, yet we all contribute to this dynamic, interdisciplinary field. My engineering background allows me to understand biological complexity in a nuanced way. I ask a biological question, but then solve it from an engineering perspective, applying different methodologies and techniques like machine learning algorithms.”

Chu received a bachelor’s and master’s degree in computer science at Beijing University of Chemical Technology, China, and then graduated with a Ph.D. in computer science and engineering from the University of Connecticut. He went on to conduct postdoctoral research under mentor Dr. Peter J. Park at Harvard Medical School. Prior to Wistar, a collaboration with a physician-scientist at Massachusetts General Hospital led to a data science position at ROME Therapeutics working in clinical drug discovery.

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