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The Wistar Institute Is Pleased to Announce the Promotion of Dr. Rahul Shinde to Assistant Professor, and the Promotions of Drs. Mohamed Abdel-Mohsen and Alessandro Gardini to Associate Professor

Wistar is honored these talented and accomplished scientists commit each day in their lab to bringing new and creative insights to cancer, immunology, and infectious disease research. Their original research makes them leaders in their fields and goes beyond scholarly achievement, to their belief in collaboration, and the creation of scientific symposia, and educational programs that expand their respective scientific fields. All promotions were effective as of January 1, 2022.

Congratulations to Dr. Rahul Shinde—Promoted to Assistant Professor

Dr. Shinde joined Wistar in June of 2019 as our first Caspar Wistar Fellow and was programmatically appointed with the Immunology Microenvironment and Metastasis Program. In his relatively short time at the Institute, Shinde established a productive laboratory, initiated numerous collaborations both in and out of Wistar, received independent NIH funding, and developed an innovative research program on the impact of the immune microenvironment in pancreatic cancer, one of the deadliest malignancies in humans. His promotion is a tangible recognition of this track record of academic excellence and a testament to the Caspar Wistar Fellow program as an innovative and successful mechanism to help foster the transition to research independence of meritorious early career investigators.

Congratulations to Dr. Mohamed Abdel-Mohsen—Promoted to Associate Professor

Dr. Abdel-Mohsen was recruited to Wistar in 2017 as a member of Vaccine and Immunotherapy Center. As a junior faculty at the Institute, Abdel-Mohsen quickly established himself as an undisputed research leader in multiple fields of investigation, with innovative and groundbreaking contributions in various aspects of HIV biology and therapy, mechanisms of immune recognition and glycomics. In his short time at Wistar, he was recognized with an impressive number of scholarly achievements, including publications in top-tier scientific literature, large extramural funding and speaking engagements at national and international venues.

Dr. Abdel-Mohsen’s energy, collaborative spirit, and engaging personality, all about the science, have made him a go-to person at our Institute, and a premiere colleague and collaborator in the broader Wistar-Penn campus.

Congratulations to Dr. Alessandro Gardini—Promoted to Associate Professor

Dr. Gardini joined the Institute in 2015, establishing a successful, internationally recognized and highly collaborative scientific program. He is a vital contributor of the Gene Expression and Regulation Program in our Cancer Center and has made seminal contributions to our understanding of novel transcriptional networks exploited in tumor development and progression. In addition to his scientific and scholarly achievements, published in top journals, Dr. Gardini has been a great ambassador of Wistar, launching an exciting Ph.D. exchange program with the University of Bologna, establishing productive research collaborations with our colleagues at the Helen F. Graham Cancer Center at Christiana Care Health and organizing a number of scientific and educational venues, including the GER Mini Symposium in 2017.

Discovering the Mechanisms That Fine-tune Gene Expression 

Turning on or off one or more genes at the wrong time or in the wrong cells can dramatically alter their activity and lead to unrestrained growth and cancer. Therefore, numerous control mechanisms are in place to keep the whole process in check.

Because of the complexity of gene expression regulation, this is one of the most intensely studied subjects.

In a new study published in the prestigious journal Cell, the lab of Dr. Alessandro Gardini and collaborators at the Peter MacCallum Cancer Centre in Melbourne, Australia, discovered a new mechanism that fine-tunes gene expression and is disrupted in cancer, indicating a possible new avenue for cancer treatment.

RNA transcription is the first step in the flow of genetic information from DNA to proteins. This is a very dynamic process operated by an enzyme called RNA polymerase II (RNAPII) and is tightly controlled through the opposing functions of several proteins. 

After starting transcription, RNAPII comes to a pause to allow the cell to check that the process is taking place smoothly and with no incidents. Shortly after, the enzyme starts transcribing again and elongating the newly synthesized RNA molecule.

Gardini and team uncovered a new regulatory checkpoint in which two proteins work in tandem to control the balance between pausing and elongation.

“Cancer is a consequence of altered gene expression,” said Gardini. “We described one of the essential ways through which gene transcription is kept in check.”

Researchers also showed that blocking one protein and activating the other at the same time represents a new potential strategy for combination treatment, demonstrating activity in preclinical models of leukemia and solid malignancies.

Overall, this study provided new insight into how gene expression is tightly controlled and opened new avenues for transcription-based anticancer therapy.

To learn more about this research, read our press release.

Wistar and Peter Mac Scientists Discover Fundamental Mechanism That Fine-tunes Gene Expression and Is Disrupted in Cancer

PHILADELPHIA and MELBOURNE, Australia — (May. 17, 2021) — A team of scientists from The Wistar Institute in Philadelphia and the Peter MacCallum Cancer Center in Melbourne, Australia, discovered a new checkpoint mechanism that fine-tunes gene transcription. As reported in a study published in Cell, a component of the Integrator protein complex tethers the protein phosphatase 2A (PP2A) to the site of transcription allowing it to stop the activity of the RNA polymerase II enzyme (RNAPII). Disruption of this mechanism leads to unrestricted gene transcription and is implicated in cancer.

The study points to new viable opportunities for therapeutic intervention demonstrating the anti-cancer effect of a new combination treatment in preclinical models of solid and hematopoietic malignancies.

Gene expression is the first step in the process by which the information encoded by a gene is used to make proteins. Controlling the timing and level of gene expression is crucial for cells to perform their specific functions within an organism, adapt to the surrounding conditions and properly respond to external stimuli.

The team, led by Alessandro Gardini, Ph.D., assistant professor in the Gene Expression & Regulation Program at The Wistar Institute, and Ricky Johnstone, Ph.D., professor, executive director of Cancer Research at the Peter MacCallum Cancer Centre, and head of The Sir Peter MacCallum Department of Oncology at the University of Melbourne, discovered a new checkpoint in the regulation of RNAPII, the enzymes that carries out transcription of DNA into RNA for gene expression.

“Cancer is a consequence of altered gene expression, as turning on or off one or more genes at the wrong time or in the wrong cells can dramatically alter their overall behavior and lead to unrestrained growth,” said Gardini. “We describe one of the essential ways through which gene transcription is kept in check.”

“We think our discovery provides new insight into how gene expression is tightly controlled,” said Johnstone. “This represents a completely new potential avenue for cancer treatment and our initial studies in mice suggested this could also improve the effect of another emerging treatment approach — CDK9 inhibition — in both blood-based and solid tumours.”

Transcription by the RNAPII enzyme takes place in several steps, each tightly controlled through the opposing functions of cyclin-dependent kinases (CDKs), which modify the enzyme by adding phosphate groups to different parts of the protein, and phosphatases that remove those phosphate groups and counteract CDK activity.

The team uncovered the involvement of a phosphatase called Protein Phosphatase 2A (PP2A) in this regulatory balance. Though PP2A performs the majority of phosphatase activities in a cell, this study provides evidence that it also plays a critical role in transcription.

CDK9 is one of the CDKs that activate RNAPII by promoting elongation, the step in which synthesis of a nascent RNA chain continues as RNAPII moves along the DNA template.

The team found that a component of Integrator, a central regulator of transcriptional processes, interacts with the PP2A phosphatase to recruit it to sites of transcription, where it counteracts CDK9 activity, and blocks transcription elongation. PP2A and CDK9 work in tandem to fine-tune the balance between activation and inhibition of transcription.

Then, researchers tested the hypothesis that targeting the PP2A-Integrator-CDK9 axis in cancer by simultaneously blocking CDK9 and activating PP2A could afford therapeutic benefit in mouse models of leukaemia and solid cancers. Combining treatment with inhibitors of CDK9 (CDK9i) and small molecule activators of PP2A (SMAPs) killed acute myeloid leukemia cells, driving prolonged therapeutic effect and significantly longer survival compared to either single agent. Similarly, combination therapy in a solid tumor model demonstrated reduced tumor growth rates and tumor volume, resulting in enhanced overall survival.

Collectively, this study describes a new fundamental mechanism of gene expression regulation and demonstrates that concomitant CDK9 inhibition and PP2A activation results in enhanced anti-cancer effects in preclinical models of both solid and hematopoietic malignancies, opening new avenues for transcription-based anticancer therapy.

Co-authors: Sarah A. Welsh (co-first author), Elisa Barbieri and Sarah Offley from The Wistar Institute; Stephin J. Vervoort (co-first author), Jennifer R. Devlin, Deborah A. Knight, Stefan Bjelosevic, Matteo Costacurta, Izabela Todorovski, Conor J. Kearney, Zheng Fan, Benjamin Blyth, Victoria McLeod, Joseph H. A. Vissers, Ben P. Martin, Gareth Gregory, Elena Demosthenous, Magnus Zethoven, Simon J. Hogg, Madison J. Kelly, Andrea Newbold, Kaylene J. Simpson, and Kieran F. Harvey from the Peter MacCallum Cancer Centre, Melbourne, Australia; Jarrod J. Sandow, Isabella Y. Kong, and Edwin D. Hawkins from The Walter and Elisa Hall Institute, Parkville, Australia; Karolina Pavic, Otto Kauko and Jukka Westermarck from University of Turku, Turku, Finland; Michael Ohlmeyer from Mount Sinai School of Medicine, New York; and Nathanael Gray from Dana Farber Cancer Institute, Boston.

Work supported by: National Institutes of Health (NIH) grants R01 HL141326 and T32-GM071339; a Research Scholar Grant, RSG-18-157-01-DMC from the American Cancer Society, The G. Harold and Leila Y. Mathers Charitable Foundation, Emerson Collective, and the Ovarian Cancer Research Alliance (Collaborative Research Development Grant #596552). Support for The Wistar Institute core facilities was provided by Cancer Center Support Grant P30 CA010815. Additional funding was provided by a Rubicon fellowship, National Health and Medical Research Council of the Australian Government, The Kids’ Cancer Project, Victorian Cancer Agency, Cancer Council of Victoria, Academy of Finland, Finnish Cancer Foundation, Finnish Cultural Foundation, Australian Cancer Research Foundation (ACRF), University of Melbourne Collaborative Research Infrastructure Program, and Peter MacCallum Cancer Centre Foundation.

Publication information: The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer, Cell (2021). Online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer 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.org.

Peter MacCallum Cancer Centre is a world-leading cancer research, education and treatment centre and Australia’s only public health service solely dedicated to caring for people affected by cancer. Petermac.org.

New Insights Into the Control of Inflammation

PHILADELPHIA — (Jan. 13, 2021) — Scientists at The Wistar Institute discovered that Early Growth Response 1 (EGR1), a protein that turns on and off specific genes during blood cell development, inhibits expression of pro-inflammatory genes in macrophages. As part of their function to protect the body against pathogens, macrophages play a major role in initiation, maintenance, and resolution of inflammation. The discovery expands the understanding of how macrophages are set off and deactivated in the inflammatory process, which is critical in many normal and pathological conditions. These findings were published online in the journal Science Advances.

“By deepening the understanding of the role of EGR1, we shed light on the fundamental process of macrophage maturation, which is required for many aspects of the immune response including inflammation,” said Alessandro Gardini, Ph.D., assistant professor in the Gene Expression & Regulation Program at The Wistar Institute and senior author on the study. “Our data suggest EGR1 acts as a master regulator of inflammation in macrophages.”

Macrophages are specialized immune cells that eliminate foreign substances, cellular debris and cancer cells. Their multi-step maturation from progenitor cells in the bone marrow requires the concerted action of critical transcription factors that regulate expression of specific genes. EGR1 is one of these factors but its function remained elusive.

In response to tissue damage and infection, white blood cells of the immune system called monocytes can leave the bloodstream and infiltrate tissues, where they undergo an elaborate developmental program and mature into macrophages. Macrophages have the ability to “eat” pathogens, promote inflammation and elicit pathogen-specific immune responses.

The molecular mechanisms underlying this maturation process are not well defined. The same set of transcription factors acting in early monocyte development were thought to be involved in the conversion of monocytes to macrophages.

Gardini and colleagues used a model to recreate differentiation of monocytes to macrophages in vitro and performed a systematic genomic analysis of the role of EGR1 in this process. They found that EGR1 binds to different DNA regulatory regions in late-differentiating macrophages as opposed to progenitor cells differentiating into monocytes.

The lab previously uncovered a mechanism whereby EGR1 regulates gene expression in monocytes and macrophages by interacting with enhancers. These are short regulatory DNA sequences that, when bound by specific transcription factors, augment the expression of the associated genes.

In the new study, researchers found that EGR1 represses inflammatory enhancers in developing and mature macrophages, blunting their activation and the immune response.

“Our results suggest that the role of EGR1 in modulating inflammation may extend beyond development of blood cells and be relevant to the control of inflammation in health and disease conditions,” said Avery Zucco, Ph.D., a postdoctoral researcher in the Gardini lab and co-first author of the study.

Co-authors: Marco Trizzino (co-first author), Sandra Deliard, Fang Wang, Elisa Barbieri, Filippo
Veglia, and Dmitry Gabrilovich from Wistar.

Work supported by: National Institutes of Health (NIH) grants R01 HL141326 and T32 CA009171; grants from the American Cancer Society (RSG-18-157-01-DMC) and The G. Harold and Leila Y. Mathers Foundation. Support for The Wistar Institute facilities was provided by Cancer Center Support Grant P30 CA010815.

Publication information: EGR1 is a gatekeeper of inflammatory enhancers in human macrophages, Science Advances (2021). Online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer 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.org.

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.