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Latest Wistar Discoveries 

Despite dramatic progress in cancer therapy, long-term survival is hindered when cancer returns. Tumor cells that escape initial treatment can travel to distant sites in the body and remain hidden there silently for years. If these "dormant" cells reawaken, they divide and give rise to new tumors, often very difficult to treat.

A new study published in Science Translational Medicine by former Wistar professor Dmitry Gabrilovich, Ph.D., and Michela Perego, Ph.D., a research assistant professor in The Wistar Institute Cancer Center, reveals that stress is one factor involved in reawakening dormant cells. They found that stress hormones can activate neutrophils, a type of immune cells, to produce certain special lipids that are in turn responsible for the reawakening dormant tumor cells. Accordingly, they observed higher levels of stress hormones and markers of neutrophil activation in the blood of cancer patients who experience early recurrence compared to patients that have late or no recurrence.

These findings suggest that stress hormone levels should be monitored in patients recovering from cancer and that keeping those hormones at bay would be beneficial to prolong remission.


Highly proliferating cancer cells within a tumor often experience severe oxygen and nutrient deprivation. To satisfy their large demands for energy generation and synthesis of molecules, cancer cells evolve to survive and continue growing using whatever nutrient sources available. Acetate is an important one.

The laboratory of Zachary T. Schug, Ph.D., assistant professor in the Molecular & Cellular Oncogenesis Program, characterized an inhibitor that targets acetate metabolism in cancer cells by blocking the function of the ACSS2 enzyme, which converts acetate into an essential metabolite used by cancer cells to generate energy.

This molecule inhibits tumor growth and causes regression in preclinical studies, demonstrating its promise as a novel therapeutic strategy for solid tumors. Study results were published in Cancer Research.


Up to 60% of ovarian clear cell carcinomas (OCCC) — the type of ovarian cancer that carries the worst prognosis — have mutations that inactivate the ARID1A tumor suppressor gene.

The laboratory of Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center, professor and leader of the Immunology, Microenvironment & Metastasis Program, discovered that mutations that inactivate ARID1A increase utilization of the glutamine amino acid, making cancer cells dependent on glutamine metabolism.

In the study, published in Nature Cancer, the team also showed that pharmacologic inhibition of glutamine metabolism may represent an effective therapeutic strategy for ARID1A-mutant ovarian cancer. The inhibitor significantly reduces tumor burden and prolongs survival in OCCC mouse models and mice carrying patient-derived tumor transplants and could become a new strategy to precisely target a specific vulnerability of OCCC cells.


Preclinical models are critical for cancer research. "Humanized" mouse models — mice with a transplanted human immune system — are used to study human-specific characteristics of the tumor microenvironment and the antitumor immune response, and to predict response to therapy.

A team led by Rajasekharan Somasundaram, Ph.D., a member of The Wistar Institute Melanoma Research Center, and Meenhard Herlyn, D.V.M., D.Sc., professor in the Cancer Center and director of The Wistar Institute Melanoma Research Center, engineered an advanced humanized mouse model to produce combinations of human cytokines that result in a more physiologically relevant model system.

Thanks to this model, they examined resistance to immunotherapy in melanoma and revealed a central role for mast cells, which are immune cells that serve as a first line of defense against pathogens. 
Researchers also showed that the use of inhibitors able to deplete mast cells can be beneficial to immune checkpoint therapy responses. These finding were published in the journal Nature Communications


Macrophages are specialized immune cells that eliminate foreign substances, cellular debris and cancer cells. As part of their function to protect the body against pathogens, macrophages play a major role in initiation, maintenance, and resolution of inflammation. Through multiple steps they mature from progenitor cells in the bone marrow and require the concerted action of critical transcription factors that regulate expression of specific genes.

Alessandro Gardini, Ph.D., assistant professor in the Gene Expression & Regulation Program, and his lab 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, blunting their activation and the immune response.

This discovery, published in Science Advances, expands the understanding of how macrophages are activated and deactivated in the inflammatory process, which is critical in many normal and pathological conditions.


Epstein-Barr Virus (EBV) establishes lifelong, latent infection in B lymphocytes, which can contribute to development of different cancer types, including Burkitt’s lymphoma, nasopharyngeal carcinoma (NPC) and Hodgkin’s lymphoma.

The Epstein-Barr Nuclear Antigen 1 (EBNA1) protein serves as an attractive therapeutic target for these cancers because it is expressed in all EBV-associated tumors, performs essential activities for tumorigenesis and there are no similar proteins in the human body.

The laboratory of Paul M. Lieberman, Ph.D., Hilary Koprowski, M.D., Endowed Professor, leader of the Gene Expression & Regulation Program, discovered an enzymatic activity of EBNA1 that was never described before, despite the intense research efforts to characterize this protein.

They found that this EBNA1 function mediates the terminal stage of viral DNA replication.

Published in Cell, this study provides new indications for inhibiting EBNA1 function, opening up fresh avenues for development of therapies to treat EBV-associated cancers.