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Wistar Scientists Explore Importance of Microglia Marker in Metastasized Brain Tumor Microenvironment


The Chen lab examines microglia activation in metastatic brain tumors

PHILADELPHIA—(Mar. 28, 2024)— The Wistar Institute’s Qing Chen, M.D., Ph.D., assistant professor in the Immunology, Microenvironment and Metastasis Program at the Ellen and Ronald Caplan Cancer Center, has discovered certain immune cells in the brain called microglia have reduced expression of TMEM119 in cases where cancer has metastasized to the brain. The Chen lab’s finding provides an opportunity to more accurately study how brain microglia behave in metastatic contexts, which is key for researching possible therapies. The new paper, “Tmem119 expression is downregulated in a subset of brain metastasis-associated microglia,” was published in the journal BMC Neuroscience.

“This research provides a new avenue and crucial first step in understanding how these immune cells interact with cancer, and we look forward to future mechanistic studies of these cases,” said Dr. Chen.

When cancer cells metastasize into the brain, the nervous system’s immune cells, called microglia, become activated. Immune cells are a very important area of study for cancer researchers because understanding how they do (or do not) function against cancer allows scientists to develop strategies to improve the immune system’s ability to fight cancer.

However, studying the mechanistic role of microglia in metastatic cancers in the brain has been difficult because, by most measures, microglia are difficult to distinguish from another set of immune cells — myeloid-derived immune cells — that also enter the brain in pathological conditions.

Dr. Chen and her lab study how cancer cells interact with brain stromal cells, and wanted to investigate TMEM119 — a cell surface marker which has been recently identified to express specifically on microglia. They aimed to investigate the TMEM119 expression in the microglia from brain metastasis tumors.

They analyzed a preclinical model of breast cancer that metastasizes to the brain, and by assessing the gene expression of the immune cells, her team was able to confirm that only brain microglia, but not infiltrated myeloid cells, express TMEM119. Moreover, metastasis-activated microglia have an identifiable reduction in TMEM119 expression.

Co-authors: Weili Ma, Jack Oswald, Angela Rios Angulo, and Qing Chen of The Wistar Institute.

Work supported by: National Institutes of Health & National Cancer Institute grants T32CA009171, R01CA241490, and Specialized Program of Research Excellence P50 CA261608.

Publication information: “Tmem119 expression is downregulated in a subset of brain metastasis-associated microglia,” from BMC Neuroscience.

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The  Wistar Institute, the first independent nonprofit biomedical research institute in the United States, marshals the talents of an international team of outstanding scientists through a highly enabled culture of biomedical collaboration and innovation, to solve some of the world’s most challenging and important problems in the field of cancer, immunology, and infectious disease, and produce groundbreaking advances in world health. Consistent with a pioneering legacy of leadership is not-for-profit biomedical research and a track record of life-saving contributions in immunology and cell biology, Wistar scientists pursue novel and courageous research research paths to life science discovery, and to accelerate the impact of early-stage discoveries by shortening the path from bench to bedside.

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Wistar Institute Study Gives New Insight into How Cancer Metastasizes to the Brain

PHILADELPHIA — (June 20, 2023) — When cancer that starts in the body metastasizes to the brain, it is almost always lethal, in part because so few treatment options exist. Now a new study by Wistar scientists published in Nature Communications shows that a type of brain cell called astrocytes plays an important role in promoting brain metastasis by recruiting a specific subpopulation of immune cells.

caplan canceThe finding could be a first step toward identifying potential targets for therapies to fight cancers that metastasize to the brain. This would fill a significant unmet need, said researcher Qing Chen, M.D., Ph.D., assistant professor, Immunology, Microenvironment & Metastasis Program, Ellen and Ronald Caplan Cancer Center at The Wistar Institute. because treatment options for brain metastasis have lagged behind, even as advances in other cancer therapies have made enormous strides, making those cancers much more treatable.

“It can be devastating for patients and their families, because they go through so much treatment, they survive the breast cancer, they all celebrate, and then it shows up in the brain,” leading to a terminal diagnosis, she said.

Several types of cancer are known for metastasizing to the brain, including breast, lung, carcinoma, and melanoma. One reason conventional treatments do not work on these cancers after they reach the brain is because the brain is such a different environment from the rest of the body, with unique brain cells (neuron and glia cells) providing different support to the metastatic cancer cells.

For the study, researchers wanted to better understand the cancer-brain interactions that trigger metastasis when cancer cells enter the brain. They focused on astrocytes, a type of star-shaped cell that helps form connections between neurons.

Using brain metastasis mouse models, researchers showed that when the astrocytes were exposed to cancer cells, they began to activate type I interferon pathways. Type I interferon, the cytokines associated with regulating inflammation, have been shown to have to anti-tumor effects. However, more and more evidence suggest controversial effects of type I IFN signaling in chronic inflammation and cancer.

“That was an exciting surprise,” Chen said, adding that it was the first time the type I interferon response had been implicated to promote brain metastasis.

They found that the interferon response was being activated at a low level but for a prolonged period of time. This could explain why a process that is normally associated with helping the immune system was actually causing harm by supporting tumor growth. Previous studies have found that low-level, chronic interferon response can cause negative health outcomes, she noted.

When they took a closer look, researchers found that the interferon signaling was activating production of a chemokine called CCL2, which in turn attracted harmful immune cells called monocytic myeloid cells. These cells promote tumor growth.

Researchers then studied mice that were genetically altered to abolish the type I interferon activation in astrocyte cells. They found that mice that were missing this pathway had fewer brain metastases.

“That shows the type I interferon response in astrocyte cells actually promotes metastasis,” Chen said.

She noted researchers found a similar result with both melanoma and breast cancer cells, showing that the process – and potential therapeutic targets – occur across different cancer types.

Chen hoped the findings encouraged more researchers to study the interactions that lead cancers to metastasize in the brain.

“It’s an urgent need to have more people pay attention to this problem, and hopefully we’ll have more basic researchers and clinicians participate in future studies, as well as more resources,” she said.

Next, Chen’s team is applying for a federal grant from the National Cancer Institute (NCI) for a follow up study to better understand the mechanism and timing of how astrocytes and the interferon response promote brain metastasis, with a goal of identifying the best therapeutic window for treating and stopping this process.

Co-authors: Wili Ma, Maria Cecilia Oliveira-Nunes, Andrew Kossenkov, and James Hayden of Wistar, Ke Xu of Boston University School of Medicine, Benjamin C. Reiner and Richard C. Crist of the University of Pennsylvania.

Work supported by: Susan G. Komen, V Foundation for Cancer Research, and the NIH/NCI.

Publication information: Type 1 interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment Nature Communications, 2023. Online publication.


The Wistar Institute, the first independent, nonprofit biomedical research institute in the United States, marshals the talents of an international team of outstanding scientists through a culture of biomedical collaboration and innovation. Wistar scientists are focused on solving some of the world’s most challenging and important problems in the field of cancer, infectious disease, and immunology. Wistar has been producing groundbreaking advances in world health for more than a century. Consistent with its legacy of leadership in biomedical research and a track record of life-saving contributions in immunology and cell biology, Wistar scientists’ early-stage discoveries shorten the path from bench to bedside.

National Institutes of Health Funding Powers Wistar Science in 2020

Approaching the end of the year, Wistar takes stock of its federal funding performance.

During the 2020 fiscal year of the National Institutes of Health (NIH) — the U.S. government agency that supports biomedical research, it funded Wistar research by granting more than $43M in existing and newly awarded grants.

“Our ability to attract and maintain federal funding is vital for the success of our enterprise and speaks volumes to the quality of the science being pursued at Wistar,” said Dario C. Altieri, M.D., president and CEO, director of the Institute’s Cancer Center and the Robert & Penny Fox Distinguished Professor. “NIH grants fuel some of our largest and most ambitious research projects and our collaborative efforts and support our Cancer Center, a powerhouse of discoveries and advanced technologies in the region.”

The NIH is made up of 27 Institutes and Centers, each with a specific research focus on particular diseases or body systems, working together to support the nation’s research efforts. The vast majority of Wistar’s active grants are administered by the National Cancer Institute (NCI), reflecting Wistar’s vast commitment to cancer research. The second largest pool of grants comes from the National Institute of Allergy and Infectious Diseases, which supports basic and applied research on infectious, immunologic and allergic diseases, powering Wistar investigations into HIV, Epstein-Barr Virus, antimicrobial resistant bacteria, and tuberculosis.

Highlights from newly awarded grants include:

  • Two large grants over four and five years, respectively, to Mohamed Abdel-Mohsen, Ph.D., assistant professor in The Wistar Institute Vaccine & Immunotherapy Center, for his glycoimmunology research in HIV. Glycoimmunology is an emerging field focused on the role of sugar molecules present at the surface of our cells, also referred to as glycans or carbohydrates, in mediating immune responses.

    The new funding will support Abdel-Mohsen’s work investigating the role of altered host sugar repertoire, or glycome, in gut and brain inflammation and cognitive disorders in HIV. This research aims to discover new mechanisms that could be targeted to prevent or treat chronic inflammation that persists in individuals living with HIV despite antiretroviral therapy.

    Applying a similar research paradigm, Abdel-Mohsen obtained additional funding to expand his research to COVID-19. He seeks to understand the integrity of the intestinal barrier in inflammation and COVID-19 pathogenesis. SARS-CoV-2 infection alters the structure of the gut wall making it more permeable to intestinal microbes that can then enter and circulate in the blood. This may lead to a loss of anti-inflammatory circulating carbohydrate molecules in the body, which results in inflammation and worse disease outcomes. This research will lay the groundwork for developing novel biomarkers for disease risk and therapeutic interventions for the COVID-19-induced cytokine storm to prevent severe outcomes and death.
  • A five-year grant to Qing Chen, M.D., Ph.D., assistant professor in The Wistar Institute Cancer Center, for her studies on brain metastasis, which causes an increasingly heavy clinical burden due to its rising incidence and the limited efficacy of existing therapies. Chen is investigating the interaction between cancer cells and the surrounding brain cells to identify key mechanisms that could be targeted to disrupt this interaction and the cancer’s ability to grow in the brain, and eventually provide more effective therapies for cancer patients.
  • A five-year grant awarded to Maureen Murphy, Ph.D., Ira Brind Professor and program leader in The Wistar Institute Cancer Center, to further her studies on the p53 protein, a master regulator of numerous functions in the cell and frequently mutated in cancer. In particular, the Murphy lab is interested in the effects of specific genetic variants of p53 on the tumor-promoting ability of the mutant p53 protein. Murphy and her team investigate how these genetic variants affect the cancer risk in different populations, and this research has important implications for informing personalized medicine approaches.
  • A five-year grant to Rugang Zhang, Ph.D., professor and deputy director of The Wistar Institute Cancer Center, that enables the Zhang lab to study the mechanisms that allow a small number of “dormant” tumor cells to persist in the body after therapy. These cells can awaken from dormancy and start proliferating to give rise to metastases even years after the onset of the primary tumor. Elucidating the underlying mechanisms of tumor dormancy is crucial to achieve cancer eradication.
  • Two NIH Pathway to Independence Awards bestowed to staff scientists Thibaut Barnoud and Sergey Karakashev, both working in Wistar Institute Cancer Center labs. This prestigious and highly sought-after award supports outstanding postdoctoral researchers in their transition from mentored training to and independent faculty position and boosts the awardees’ competitiveness in the job market

The information on dollar amounts disclosed in this blog is publicly available and has been obtained through the NIH Research Portfolio Online Reporting Tools (RePORT).

A New Generation of Cancer Researchers at Wistar

Expanding the faculty and enhancing its multidisciplinary nature are focal points in Wistar’s Cancer Center under the leadership of Dario Altieri, M.D., president and CEO, director of The Wistar Institute Cancer Center, and Robert and Penny Fox Distinguished Professor.

The recent recruitment efforts, supported by partners such as The Pew Charitable Trusts, were inspired by the idea that junior investigators—in their peak of scientific productivity and creativity—are most likely to generate cutting-edge research. Therefore, attracting the most brilliant scientists and persuading them to launch their laboratory at Wistar positions the Institute ahead of a trend that is becoming increasingly popular in many research institutions.

In the span of one year from 2015 to 2016, four assistant professors joined the Cancer Center, thereby enriching and complementing existing programs with new expertise and fresh perspectives:

Qing Chen, M.D., Ph.D., came to Wistar from Memorial Sloan-Kettering Cancer Center and started her lab researching the mechanisms of brain metastasis, a very challenging subject that is in urgent need of advancement.

Alessandro Gardini, Ph.D., an ‘old acquaintance’ of Wistar’s, began his postdoctoral training in a Wistar lab and completed it at the University of Miami. He studies genomics and epigenetics, or how our genome is decoded and how malfunctioning mechanisms can cause cancer.

Kavitha Sarma, Ph.D., came from Harvard Medical School. She is a biochemist and an epigenetics expert. Her current focus is in understanding how certain RNA molecules help shape the structure of chromatin, the combination of DNA and protein that makes up chromosomes, and elucidating the role of these mechanisms in cancer and other diseases.

Zachary Schug, Ph.D., a Philadelphia native who received his postdoctoral training across the ocean at the Beatson Institute in Glasgow, U.K., returned to Philadelphia to launch his research program at Wistar in cancer metabolism, looking at the mechanisms that support the high nutrient demands of tumor growth.

Four years after arriving, and well-settled at Wistar, these four assistant professors have made
significant progress establishing research programs, publishing their first papers as senior authors, and securing solid funding through federal grants and private foundations, such as the W. W. Smith Charitable Trusts, the American Cancer Society, Susan G. Komen, the V Foundation for Cancer Research, and The G. Harold & Leila Y. Mathers Foundation.

We brought the four scientists together to take stock of their experiences at Wistar.

A diverse and stimulating scientific environment

One of the common themes in the conversation was the intellectual and scientific support junior investigators receive at the Institute. “Wistar is a small place with exceptional scientific diversity,” said Gardini.

“Exposure to different expertise in a highly collaborative environment has created plenty of opportunities for me to expand my scientific horizon and skillset,” added Schug. “For example, because of the outstanding immunology community we have at the Institute and the frequent seminars they host, my knowledge of immunology has expanded dramatically, and that was an area in which I wanted to grow.”

“I kept myself distant from immunology until I joined Wistar; it wasn’t my favorite field,” joked Chen. “But no cancer biologist can stay away from immunology these days, especially if you study the tumor microenvironment like I do. Being at Wistar made that transition easier for me.”

Pursuing their projects and expanding their interests

When asked if they stayed their course and followed their original research plan, all four scientists said they are working on the overall ideas they proposed, but they’ve added new directions they can now pursue because of the expertise and support of other labs at the Institute.

“My drug development project was difficult to get off the ground,” said Schug. “At Wistar, though, through collaboration with Dr. Salvino, I took a different approach that was successful.”

When you are a basic research scientist, finding good model systems to test your hypothesis can really make a difference. “I felt safe exploring the ovarian cancer model because there is a lot of expertise in Dr. Zhang’s lab, in particular, and I can count on resources for future developments,”added Gardini.

“Even though my primary interest is breast cancer, I received a lot of mentorship from Dr. Weeraratna,” said Chen. “She brought me into melanoma—a great model to study brain metastasis because of its tendency to invade the brain. As a matter of fact, nearly 40% of melanoma patients develop brain metastasis.”

What about academic freedom, we asked. Everyone said they were given leeway to choose their scientific direction and explore their ideas.

Sometimes, access to funding can bring about involuntary restraints to the scientists’ ability to pursue their interests. “Access to funds for basic researchers can be a challenge because most of the money is diverted to applied research,” said Sarma.

“My work is clinically relevant, so I don’t necessarily face this issue,” added Chen. “Yet, I can’t wrap my head around the scarcity of funding for basic research, as it creates the foundations for clinical development.”

“I appreciate the Institute’s strategy for grant submission because we are not pushed to apply to every possible opportunity, but they encourage us to focus our efforts where we are stronger and have a better chance of success,” said Gardini. “In the long run, it’s an efficient approach and avoids putting too much pressure on the junior faculty members.”

A little weight off their shoulders

Technological and administrative support were also highly rated and considered crucial for growth and success.

“Wistar has a reputation for its core facilities, and they absolutely lived up to my expectations,” said Gardini. “Besides the quality of their work, their efficiency and fast turnaround help getting answers fast and moving the projects forward.”

“Dario kept his promise in terms of equipment and facilities,” said Schug. “Having a metabolomics core was a necessity for the research I wanted to pursue, and he and other professors worked with me to secure funding for new state-of-the-art instrumentation. Dario has been very supportive of me setting up new techniques at the Institute.”

Administrative support is very important for junior principal investigators who are starting to navigate grants and budget, and managing multiple projects and tasks at the same time. “The support we receive from the administrative departments is exceptional, it makes our lives easier so we can focus on the science as much as possible,” said Sarma.

Beyond Wistar

Expanding beyond Wistar’s walls and into the Philadelphia life sciences hub, there was consensus that, with so many academic research institutions and hospitals, most of which are expanding, Philadelphia is the place for biomedical scientists. “I have ongoing collaborations with nearly all the major cancer centers in Philadelphia at this point,” said Schug. “It’s as easy as going across the street or taking a walk downtown.”

“If my projects lead me in a new direction that I want to explore, there is a very high chance I’ll be able to find someone around who can help,” added Gardini.

The private biotech arena is also bourgeoning in Philly. “I’m not quite there yet,” said Schug. “Though I definitely see my research expanding in that direction. We are actively engaged in drug development and testing our compounds in preclinical models with the hope that in a year from now we may begin searching for a biotech or pharmaceutical company with which to partner. Fortunately, Wistar has a fantastic business development team that supports us throughout this process.”

“I’m not exposed to biotech now, maybe in the future, if my studies identify new therapeutic targets,” said Chen.

“Alessandro and I are a little less likely to benefit from it because of the basic nature of our science and the fact that the biotech industry in Philadelphia is geared towards drug development. Naturally, it can have a bigger impact on translational scientists,” said Sarma.

A home for basic research

Bringing basic investigators on board reflects Wistar’s everlasting commitment to fundamental research and the type of breakthroughs that can come from it. In addition to expanding the universal knowledge of biological mechanisms, basic discoveries point to new therapeutic targets that can be drugged, while bringing about technological advancement.

“Genomics is a very technology-driven field,” said Sarma. “I’m excited to witness and participate in this trend and always thrilled to see new technologies emerge that will allow us to explore biological phenomena and disease in greater depth.”

“We can now look at things in ways scientists have never before, we can do genomic analysis at the single-cell level, which is mind-blowing.” added Gardini. “Obviously, this also makes our work challenging, because we need to keep up with the fast pace of technology and stay abreast of new developments and incorporate them in our research in meaningful ways.”

A look at the future

“I am very excited about the developments of my research on how diet, metabolism, microbiome, and epigenetics talk to one another in cancer,” said Schug. “Speaking of new technologies, we have been advancing new tools to study the organism as a whole and I am eager to apply this new approach to my research at Wistar.”

“I’m happy that more labs are working on brain metastasis, and I look forward to more neurobiologists entering the field,” said Chen. “Looking at things just from the cancer angle is limiting, we can move forward much faster when we know the underlying physiology.”

“Cancer genomics studies in the past decade have highlighted that many transcriptional and chromatin modulators are mutated in cancer, and for the vast majority of these we don’t know what their role is,” said Gardini. “The field is getting more and more competitive, but I’m excited that there is so much room to explore and figure out new mechanisms, and with that also come growing funding opportunities.”

“I get excited about every new discovery, big and small,” said Sarma. “Having the first piece of data and looking at it for the first time is a lot of fun, and I look forward to more of these moments. I love figuring out how things work, solving puzzles, making sense of unexpected results. That’s the best part of my job.”

The gang

Maybe it’s because they arrived within a few months of each other, or maybe it’s because they are all first-time independent investigators launching their career in academia together, and it’s certainly because they get along well—but the fab four have formed a strong bond.

“Besides collaborating scientifically, I think we’ve created a support system for each other,” said Sarma. “We interact daily and make time to connect and discuss each other’s strategies and little bumps in the road.”

“They have dragged me out of my shell, and I’m glad they did that,” said Chen. “Someone will check if they haven’t seen me for a while.”

“I’ve received a lot of help on grants applications from these guys,” said Schug. “We exchange tips and learn from each other’s experiences.”

“We root for each other’s successes and celebrate each other’s accomplishments, which is not to be taken for granted,” said Gardini. “This reflects positively on the way I feel about Wistar.”

“We don’t just talk about science, though,” said Sarma. “We discuss work-life balance, vacations, and our lives and hobbies outside the lab.”

“I’m going to say that food is probably our most typical conversation subject,” interjected Gardini, and they all acknowledged that with a laugh.

$12.5 Million Grant Awarded to Wistar Extends Federal Support of the Institute’s Quest for Improved Targeted Therapies for Melanoma 

PHILADELPHIA — (Oct. 17, 2019) — The Wistar Institute and collaborating institutions have received a major grant from the National Institutes of Health to further research on new melanoma targeted therapies integrating the role of the tumor microenvironment in influencing response to therapy and development of resistance.

The grant, totaling $12.5 million over five years, is a collaborative, multidisciplinary research program that supports multiple research projects contributing to the overall objectives.

The collaboration team is led by Meenhard Herlyn, D.V.M., D.Sc., Director of Wistar’s Melanoma Research Center and Professor in the Molecular & Cellular Oncogenesis Program, and Ashani T. Weeraratna, Ph.D., Bloomberg Distinguished Professor of Cancer Biology and the E.V. McCollum Chair of Biochemistry & Molecular Biology at the Johns Hopkins Bloomberg School of Public Health, and co-program leader of the Cancer Invasion and Metastasis Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, School of Medicine. Until very recently, Dr. Weeraratna was a member of Wistar’s faculty.

Even though the breakthroughs in immunotherapy and targeted therapy have improved the overall outcome for patients, a significant fraction of them fail to respond or develop resistance to frontline therapy.

“Tumor cells and immune cells communicate and interact with the other cell populations in the environment surrounding the tumor,” said Herlyn. “Therefore, just targeting specific genetic drivers in the tumor cells or specific immune response mechanisms is not effective because the tumor eventually finds ways to bypass the block. Our team brings together diverse expertise so that we can tackle the whole picture from different angles.”

This funding is an extension of a pre-existing grant that has continuously been funded for 10 years and has produced numerous advancements in the field.

“We are excited to deploy our expertise in the tumor microenvironment to hone and improve existing therapies for melanoma,” said Weeraratna. “We also plan to identify novel targets so as to disrupt the age-related changes that drive therapy resistance commonly seen in older melanoma patients.”

During the previous funding cycle, the team revealed the impact of aging on the tumor microenvironment, defined metabolic mechanisms that influence tumor cell survival and immune cell regulation and identified several novel molecular targets and potential inhibitors.

Building on their new understanding of the role of the tumor microenvironment in therapy resistance, researchers are now expanding their studies through four integrated projects that aim to:

  • Target the lipid metabolism in immune cell populations that favor tumor growth as a way to inhibit their function;
  • Block lysosomal pathways that allow melanoma cells to recycle nutrients and survive in stress conditions;
  • Advance development of a molecule that has been proven effective in selectively killing melanoma cells and test it on difficult-to-treat melanoma types;
  • Target mechanisms through which melanoma cells circumvent the activity of MEK inhibitors, to overcome resistance and lack of response to therapy.

Projects co-leaders on the grant are: Wistar investigators Maureen Murphy, Ph.D., leader of the Molecular & Cellular Oncogenesis Program and the Ira Brind Professor; Dmitry Gabrilovich, M.D., Ph.D., leader of the Immunology, Microenvironment & Metastasis Program and the Christopher M. Davis Professor, Jessie Villanueva, Ph.D., associate professor in the Molecular & Cellular Oncogenesis Program; from University of Pennsylvania: professor Jeffrey D. Winkler, Ph.D., associate professor Ravi K. Amaravadi, M.D., and associate professor Donna L. George, Ph.D.; and from Thomas Jefferson University: professor Andrew Aplin, Ph.D. Cores are led by Herlyn, Weeraratna and Qin Liu, M.D., Ph.D., from Wistar, and Xiaowei Xu, M.D. Ph.D., from University of Pennsylvania. Co-investigators include Zachary Schug, Ph.D., Qing Chen, M.D., Ph.D., and Joseph Salvino, Ph.D., from Wistar.

Grant information: 2P01CA114046-11A1, Targeted Therapies in Melanoma, 2008-2024.


The Wistar Institute is an international leader in biomedical research with special cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible.

New Mechanism Fueling Brain Metastasis Discovered at Wistar

PHILADELPHIA — (Oct. 9, 2019) — Scientists at The Wistar Institute described a novel mechanism through which astrocytes, the most abundant supporting cells in the brain, also promote cancer cell growth and metastasis in the brain. According to a study published online in the journal Cancer Discovery, astrocytes provide fatty acids that activate the PPAR-gamma pathway in cancer cells, enhancing their proliferation.

Brain metastasis remains an important contributor to overall cancer mortality in patients with advanced-stage disease, especially lung, breast, colon and kidney carcinoma, and melanoma. Current therapeutic strategies have shown limited efficacy, underscoring the need to expand our knowledge of brain metastasis mechanisms to identify novel therapeutic targets.

“We know that cancer cells take advantage of the interaction with local cells, especially astrocytes, to survive and proliferate in the brain environment,” said Qing Chen, M.D., Ph.D., assistant professor in the Immunology, Microenvironment & Metastasis Program and senior author of the study. “We wanted to understand the nature of this interaction and what exactly astrocytes provide to support metastatic growth.”

Chen and her collaborators focused on clinically relevant mouse models of melanoma brain metastasis and showed that astrocytes promoted cancer cell proliferation. By investigating the molecular mechanisms of this interaction, they found that the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) pathway is activated in cancer cells that possess elevated ability to form brain metastasis, and it is even more active when these cells are co-cultured with astrocytes.

Genetic and pharmacologic blockade of PPAR-gamma signaling resulted in decreased cancer cell growth and a reduced response to astrocyte-induced proliferative effect, establishing the functional relevance of this pathway in brain metastasis.

The brain is the fattiest organ in the body, enriched in polyunsaturated fatty acids that are needed to support its functions. Astrocytes are a major cellular source of fatty acids. The team showed that polyunsaturated fatty acids released by astrocytes activate PPAR-gamma signaling in cancer cells, which in turn results in enhanced proliferation.

“Our data support that brain metastatic cells take advantage of the high fat supply provided by astrocytes as a nutrient source for their metabolism and growth,” said Yongkang Zou, Ph.D., a postdoctoral fellow in the Chen lab and first author of the study.

Importantly, comparing normal skin, benign nevus, primary tumors, extracranial metastasis, and brain metastasis samples from melanoma patients, the team confirmed the highest PPAR-gamma levels in brain metastatic lesion.

Furthermore, treatment of mouse models of melanoma and breast cancer brain metastasis with a PPAR-gamma inhibitor decreased the metastatic burden and was well tolerated.

“Previous studies have indicated a tumor-suppressive function for PPAR-gamma in primary tumors,” said Chen. “Our work suggests that this pathway may play an opposite role in metastatic cells, particularly in the lipid-rich brain environment, and highlights PPAR-gamma as a viable therapeutic target to control brain metastasis.”

Co-authors: Andrea Watters, Nan Cheng, Caroline E. Perry, Gretchen M. Alicea, Joshua L.D. Parris, Meenhard Herlyn, Maureen E. Murphy, Zachary T. Schug from Wistar and Ashani T. Weeraratna, formerly at Wistar; Ke Xu from Boston University School of Medicine; Ezra Baraban, Anupma Nayak and Xiaowei Xu from the Perelman School of Medicine of the University of Pennsylvania.

Work supported by: National Institutes of Health (NIH) grant T32 CA009171 and grants from Susan G. Komen (CCR17487999), JAYNE KOSKINAS TED GIOVANIS FOUNDATION FOR HEALTH AND POLICY, a Maryland private foundation dedicated to effecting change in the health care industry for the greater public good, and the V Foundation for Cancer Research. Additional funding was provided by the Ching Jer Chern Memorial Award. Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815.

Publication information: Polyunsaturated Fatty Acids from Astrocytes Activate PPAR Gamma Signaling in Cancer Cells to Promote Brain Metastasis, Cancer Discovery (2019). Online publication.


The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. Wistar’s Business Development team is dedicated to accelerating the translation of Wistar discoveries into innovative medicines and healthcare solutions through licensing, start-ups and creative collaborations.

The Wistar Institute Secures More Than $4.2M in Philanthropic Support

PHILADELPHIA — (July 3, 2019) —The Wistar Institute, an international leader in biomedical research on cancer, immunology and infectious disease, has received more than $4.2 million in non-federal funding awarded by private foundations.

  • Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center and professor & co-leader of the Gene Expression & Regulation Program, is the principal investigator on a three-year collaborative research development grant from the Ovarian Cancer Research Alliance. This grant totaling $900,000 will support in-depth research on the molecular mechanism of some key epigenetic regulators in ovarian cancer to identify potential targets for novel therapeutic strategies.
  • Alessandro Gardini, Ph.D., assistant professor in the Gene Expression & Regulation Program, was awarded a three-year, $825,000 grant from the G. Harold and Leila Y. Mathers Foundation in support of his research to identify new factors and mechanisms that regulate maturation of stem cells into blood and immune cells. Gardini also received an American Cancer Society Research Scholar Award for $792,000 over four years to study the role of the ARID1A protein in ovarian cancer.
  • Zachary Schug, Ph.D., assistant professor in the Molecular & Cellular Oncogenesis Program, received a Susan G. Komen Career Catalyst Award that will support his research for three years with $450,000. In addition, Schug was awarded a $110,000 grant from the W.W. Smith Charitable Trust. Both of these awards will support his work on tumor cell metabolism to expose new vulnerabilities that could be therapeutically targeted as more effective treatment options for patients with breast cancer, melanoma and acute myeloid leukemia.
  • David B. Weiner, Ph.D., Wistar executive vice president, director of the Vaccine & Immunotherapy Center, and the W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute, was the recipient of a subaward from a grant from the Bill & Melinda Gates Foundation awarded to Inovio Pharmaceuticals, Inc. This funding will provide support for a total of $414,000 to apply the DMAb technology developed at Wistar to develop an immunotherapeutic strategy against influenza.
  • Makan Khoshnejad, Ph.D., staff scientist in the Vaccine & Immunotherapy Center at Wistar, received a $231,000 grant over three years from the American Heart Association to fund research on a novel type of lipid-lowering therapeutics based on synthetic DNA technology developed at Wistar.
  • Qing Chen, M.D., Ph.D., assistant professor in the Immunology, Microenvironment & Metastasis Program, was granted a two-year award totaling $200,000 from the V Foundation for Cancer Research in support of a research project to develop methods for the visualization of interactions between tumor cells and brain cells during brain metastasis.
  • Mohamed Abdel-Mohsen, Ph.D., assistant professor in the Vaccine & Immunotherapy Center, was awarded a $130,000 grant over two years from amfAR, The Foundation for AIDS Research, to identify new biomarkers that can help predict the time in which HIV rebounds after treatment interruption.
  • Daniel Kulp, Ph.D., associate professor in the Vaccine & Immunotherapy Center, received a $110,000 grant from the W.W. Smith Charitable Trust to advance a structure-based HIV vaccine strategy.
  • Shuai Wu, Ph.D., postdoctoral fellow in the Zhang laboratory was awarded a $75,000 grant from the Ovarian Cancer Research Alliance to develop a new therapeutic strategy based on combination of two targeted inhibitors for ovarian cancer with mutations in the ARID1A gene.
  • The Institute received a $20,000 grant from the Fred J. Brotherton Charitable Foundation in support of Wistar’s Biomedical Technician Training Program that prepares college students to become research assistants in the biomedical field.