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Wistar Scientists Study What Cancer Cells Crave

Written by The Wistar Institute on . Posted in Featured News.

Wistar’s Zachary Schug and lab are studying the relationship between alcohol intake and some site-specific cancers

What do cancer cells need to thrive and grow? The Wistar Institute’s Zachary Schug, Ph.D. — assistant professor in the Molecular and Cellular Oncogenesis Program at Wistar’s Ellen and Ronald Caplan Cancer Center — studies how cancer cells’ metabolism works and what cancer cells use for fuel. His lab is on a quest to understand how cancer cells process a nutrient called acetate. We sat down with Dr. Schug to talk about his work in the field of cancer metabolism and its relationship with our daily eating and drinking habits.

What is your lab discovering about what cancer cells need to thrive on and grow?

As researchers who study cancer metabolism, we’re interested in understanding and then hopefully stopping cancer cells from taking advantage of the nutrients available to them to grow and spread. We focus on acetate, a compound that forms when your body processes alcohol; when you drink, acetate is the main thing that alcohol gets broken down into. The liver has a high amount of acetate-metabolizing genes because that’s where our bodies detoxify alcohol.

When you binge drink alcohol, the acetate levels in your blood skyrocket, and acetate goes from being a nobody to a somebody. Both healthy cells and cancer cells can metabolize acetate, depending on the cell type, but we’ve seen certain cancers — including certain breast cancers, melanomas, and even blood cancers — express these acetate-metabolizing genes.

We think drinking alcohol might add fuel to the fire for precancerous or cancerous cells by giving them access to an abundance of acetate. It may accelerate their ability to take advantage of this alternative nutrient source to grow; that’s where we think part of the risk between alcohol and cancer comes from and where we need more research. Cancer adapts and changes over time to survive, so if a cancer is benefitting from acetate metabolism, it can increase the expression of the genes that let it take advantage of that.

My lab works on selectively stopping acetate metabolism in cancer, which we’ve been able to carry out both with gene editing and by designing a small molecule inhibitor with our collaborators as a possible drug candidate.

How does alcohol increase your risk for cancer?

That’s the big question I’m focused on. We know that alcohol correlates with cancer risk. But getting the data to confirm how alcohol puts you at risk, at the molecular level — what we rely on to come up with potential therapies — has been surprisingly difficult.

We have good granular data on alcohol use from people suffering from alcoholism specifically, but the general clinical data on alcohol use for cancer patients — that’s a lot less well characterized. Knowing the difference between someone who has a glass of wine with dinner five nights a week and someone who has five cocktails after work on Friday is especially important for gauging acetate levels, possible health impacts, etc.

We also have concerns about alcohol and acetate in the context of cancer remission. What if there are some cancer cells left behind that are predisposed to using acetate for their growth? Then continuing to drink or even increasing one’s amount of alcohol consumption could be a major risk — one we need to understand better so people can make informed decisions.

We are collaborating with the Philadelphia VA Medical Center and ChristianaCare for cancer patient blood samples, and I’m hopeful that, by collecting detailed survey data on their drinking habits in combination with analyzing their metabolic profiles we’ll be able to get a better understanding of the risk mechanics of alcohol.

Are there other possible health effects from acetate?

We think cancer isn’t the only thing involved in alcohol–acetate signaling. Because many bacteria also produce acetate as a by-product of bacterial metabolism, the immune system, when it sees a spike in acetate levels, can take that as a signal to combat infection. But if someone has chronic exposure to elevated acetate, it becomes a “boy who cried wolf” situation: the immune system starts to get used to higher levels of acetate as a new normal, which we think can put someone at greater risk for infections.

It’s worth considering our dietary and drinking habits carefully in light of realistic risks. This is why granular biomedical research is so important: once we understand what happens at the molecular level — X causes Y, which leads to Z — we have a much better picture of how to assess and combat risks to human health.

Wistar Researchers Discover Possible New Treatment for Triple-Negative Breast Cancer 

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA—(Sep. 18, 2023)—Zachary Schug, Ph.D., assistant professor in the Molecular and Cellular Oncogenesis Program of the Ellen and Ronald Caplan Cancer Center at The Wistar Institute, has published a new paper in the journal Nature Cancer. Schug’s paper — titled, “Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer” — demonstrates a double-acting mechanism for fighting a particularly aggressive, difficult-to-treat form of breast cancer. Schug’s research shows how silencing a certain gene, ACSS2, may improve existing treatments for patients.

Triple-negative breast cancer, or TNBC, affects 10-15% of patients with breast cancer in the US. TNBC is called “triple-negative” because the cancer lacks an estrogen receptor, a progesterone receptor, and a HER2 (human epidermal growth factor) receptor. The absence of any of these receptors — receptors that, when present in other forms of breast cancer, can be effectively targeted during treatment — makes treating TNBC quite difficult, and patients with TNBC have limited treatment options. TNBC’s notorious aggression makes the technical challenge of finding a reliably effective treatment target all the more serious: compared to other breast cancers, TNBC grows faster and resists treatment more stubbornly. All these factors contribute to the fact that TNBC patients suffer from worse prognoses.

But Zachary Schug, Ph.D., and co-authors have demonstrated the efficacy of a double-acting concept: silencing the gene ACSS2 impairs TNBC metabolism while simultaneously boosting the immune system’s ability to fight it. ACSS2 regulates acetate, a nutrient that cancer cells — and TNBC cells in particular — take advantage of to grow and spread. Schug and his team used two methods to de-activate ACSS2: CRISPR-Cas9 gene editing, and the compound VY-3-135, a potent ACSS2 inhibitor identified by Schug and his colleagues in 2021.

The researchers found that targeting ACSS2 in this preclinical study not only hampered this aggressive cancer’s ability to metabolize acetate and grow — it also triggered the immune system to recognize and attack the cancer. Because cancer cells with inhibited ACSS2 can’t process acetate very well, the tumor region becomes bathed in acetate, which alerts the immune system of something amiss.

This process of guiding the immune system to the cancer — called “immunosensitization” — has confounded other TNBC researchers. But Schug’s approach showed that ACSS2 inhibition immunosensitized against TNBC so well that tumor growth was drastically reduced, even to the point of wiping out the cancer completely in some experiments.

“Basically, we’ve proved that the immune system can take advantage of acetate that the tumor can’t process. It kicks the cancer while it’s down,” said Schug. “In fact, the immune system does this so well that it remembers how to attack TNBC in the future — even if that tumor’s ACSS2 gene is still active.”

Another group’s different ACSS2-inhibiting approach is in human clinical trials, and Schug’s research shows how ACSS2-inhibiting treatment might be able to improve outcomes for patients diagnosed with the infamous TNBC. By testing ACSS2 inhibitors alongside standard anti-breast-cancer chemotherapy, Schug et al. found that ACSS2 inhibition enhanced the treatment’s effectiveness.

“We knew that ACSS2 was a promising target for TNBC. Our research shows us how the immune effects of ACSS2 inhibition could eventually be used in for TNBC patients with limited treatment options,” said Schug. “More research is needed, but by combining this approach with other cancer therapies, we expect to see big improvements in treating TNBC.”

Co-authors: Katelyn D. Miller, Seamus O’Connor, Katherine A. Pniewski, Toshitha Kannan, Reyes Acosta, Gauri Mirji, Sara Papp, Michael Hulse, Fabrizio Bertolazzi, Yellamelli V. V. Srikanth, Rahul S. Shinde, Daniel T. Claiborne, Andrew Kossenkov, Joseph M. Salvino and Zachary T. Schug of The Wistar Institute; Fabrizio Bertolazzi of the University of Bologna; and Steven Zhao and Kathryn E. Wellen of the University of Pennsylvania.

Work supported by: This work was supported by grants from the National Institutes of Health (NIH) National Cancer Institute (NCI) DP2 CA249950-01, NIH NCI P01 CA114046, NIH R21 CA259240-01, the W.W. Smith Charitable Trust, Susan G. Komen CCR19608782 and the V Foundation for Cancer Research. This research and project is funded, in part, by a contract with the Pennsylvania Breast Cancer Coalition. The PBCC takes no part in and is in no way responsible for any analyses, interpretations or conclusions contained herein. We acknowledge funding from the NIH NCI T32 CA009171 and the American Cancer Society Rena and Victor Damone Postdoctoral Fellowship PF-20-1225-01-CCG. The Wistar Molecular Screening Facility and Genomics Facility are supported by NIH grant P30 CA010815. The Wistar Proteomic and Metabolomic Facility is supported, in part, by NIH grants R50 CA221838 and S10OD023586. The HIC is supported, in part, by NIH P30 AI045008 and P30 CA016520.

Publication information: “Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer” from Nature Cancer

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Fighting Breast Cancer Disparities Through Collaboration

Written by The Wistar Institute on . Posted in Featured News.

A decade-long collaboration between Wistar and ChristianaCare is leading to new discoveries and better treatment for triple-negative breast cancer patients.

Dario C. Altieri, M.D., president, CEO, and director of the Ellen and Ronald Caplan Cancer Center at The Wistar Institute, and Nicholas J. Petrelli, M.D., Bank of America endowed medical director of the Helen F. Graham Cancer Center & Research Institute at ChristianaCare, formed a collaboration between the two institutions that would expedite the pipeline of cancer interventions from bench to bedside.

“We had the patients, and they had the world-class science,” said Petrelli. “We felt that this was a great opportunity between an NCI-designated, basic science research center and an NCI community cancer center. This relationship is unique in cancer research.”

This collaboration has yielded more than a dozen translational cancer research papers to date and advanced research discoveries made in Wistar labs into early clinical trials at ChristianaCare. One of the newest projects to come from this collaboration is a population health study on treating triple-negative breast cancer.

RESEARCHING TRIPLE-NEGATIVE BREAST CANCER

Triple-negative breast cancer is an aggressive form of breast cancer with few treatment options. It’s more than twice as common in Black women as in white women, and Black women have a 40% higher mortality rate [1, 2]. These factors are what led Zachary Schug, Ph.D., an assistant professor in the Molecular and Cellular Oncogenesis Program at Wistar’s Ellen and Ronald Caplan Cancer Center; Jennifer Sims-Mourtada, Ph.D., lead scientist and director of Translational Breast Cancer Research at ChristianaCare’s Helen F. Graham Center & Research Institute; and Scott Siegel, Ph.D., MHCDS, director of population health research at ChristianaCare to join forces.

Siegel says, “Disparities in breast cancer are the result of multiple interacting factors operating at different scales, so if we’re going to do something meaningful, we can’t take a silo-based approach and focus on one key variable. We really do need to look across this spectrum.”

ALCOHOL AND BREAST CANCER

Schug, Sims-Mourtada, and Siegel share three intersecting research interests: breast cancer, health disparities, and investigating the connection between alcohol and cancer – truly the linking factor in the context of this project.

As a molecular and cellular biologist, Schug examines the problem of alcohol and breast cancer at the “smallest” level of the three researchers. His research has shown that breast tumors feed on a breakdown product of alcohol called acetate, which they use to grow and fight the body’s immune responses. How and why the breast cancer cells use acetate in this way are questions Schug continues to pursue. However, it’s important for him to make his work clinically meaningful as quickly as possible.

“Instead of just focusing on individual tumor cells and trying to do things at a molecular level, we wanted to ask more broad questions,” Schug explains, “and that’s where Scott and Jen come in with what they’re doing.”

GENETICS AND ALCOHOL METABOLISM

Sims-Mourtada is a translational breast cancer researcher who studies how gene expression regulates and alters the progression of breast cancer. Her work intersects neatly with Schug’s because she is investigating whether race-based differences at the genetic level affect how many alcohol-metabolizing enzymes are produced in breast cancer stem cells.

“We have some data that show that a certain isoform of enzyme is overexpressed in tumors from Black women, and a possible reason for this could be some kind of genetic factor,” said Sims-Mourtada. Specifically, there are reports from alcohol use disorder research suggesting the existence of tiny genetic variations called single nucleotide polymorphisms (SNPs) that may be involved in alcohol metabolism. Sims-Mourtada is working on identifying SNPs that might cause an alcohol-metabolizing gene to become overactive or underactive in individuals of differing races which, combined with the individual’s alcohol use, could increase tumor growth.

ALCOHOL-RELATED ENVIRONMENTS AND BEHAVIORS

Siegel looks at the problem of triple-negative breast cancer at a population level. His research focuses on identifying modifiable risk factors for cancer—i.e., whether people’s cancers can be affected by where they live and what they do.

“My contribution to this project is to collect behavioral data on patients. Then we can relate these variables to the processes Jennifer and Zach are looking at, including the enzymes that metabolize alcohol and ultimately the metabolites,” said Siegel.

In examining prevalence of triple-negative breast cancer within ChristianaCare’s home state of Delaware, he found that the areas that have the highest rates of this cancer also have the highest rates of alcohol use disorder and the highest density of alcohol retail stores. The collaboration will help to dig into the biology and genetics that may belie this correlation.

THE RESEARCH PROJECT

The researchers plan to recruit 1,000 women with breast cancer, 500 Black and 500 white. They will biopsy the women’s tumors, which Sims-Mourtada will use to examine differences in gene expression by race. They will also take blood, which Schug will analyze for levels of ethanol and acetate in order to assess the patient’s drinking level, as well as nutrients to get a sense of the patient’s diet. Finally, the researchers will collect extensive patient reported data – including lifestyle, environmental, and socioeconomic factors – which Siegel will assess to determine how the patient’s behaviors and environment relate to what is happening inside their body.

“I think it’s a unique approach to be looking at this multi-level analysis. We’re not just taking into consideration the neighborhood or the behavior, but how those influence what actually happens biologically and genetically,” said Sims-Mourtada.

IMPACTING PATIENTS, PROVIDERS, AND COMMUNITIES

At a patient level, the researchers are hoping to identify biomarkers that would not only indicate risk of developing triple-negative breast cancer but also help detect the cancer sooner than is currently possible via conventional methods.

“Triple-negative breast cancer may start earlier in life before mammography is recommended or develop between screenings. To be able to do a blood test the way one could do a cholesterol test for heart disease, maybe we can see cancer developing sooner,” said Siegel.

The researchers also want to uncover risk factors that healthcare providers can use to educate patients and steer them toward behaviors that match their individual risk level. Alcohol consumption won’t necessarily increase cancer risk for everyone. But it will for some, and those individuals should be informed. With just gentle nudges from a physician, simple changes in alcohol consumption could save lives by reducing the probability of breast cancer in certain high-risk individuals.

At a community level, identifying where rates of risk for triple-negative cancer are highest could mean more targeted outreach. To be able to use public health resources in the areas where they could make the biggest impact could amplify effects on many lives.

A LASTING COLLABORATION

Wistar and ChristianaCare’s joint efforts have repeatedly yielded a two-way benefit: basic scientists learn directly from clinicians about the issues clinicians are seeing at the bedside, and the clinicians learn from the scientists about the challenges scientists face as they are trying
to solve problems in the quest for therapeutic solutions.

“We will be publishing in basic science journals, but we will also be changing how we practice in the cancer center, potentially how we do our community outreach, and possibly prevent loss of life as a result of this research,” said Siegel.

“It really has been a special marriage made in heaven,” said Petrelli, “and I see it continuing for a long time.”

SOURCES

  1. McCarthy, A. M., Friebel-Klingner, T., Ehsan, S., He, W., Welch, M., Chen, J., Kontos, D., Domchek, S. M., Conant, E. F., Semine, A., Hughes, K., Bardia, A., Lehman, C., & Armstrong, K. (2021). Relationship of established risk factors with breast cancer subtypes. Cancer Medicine, 10(18), 6456–6467. https://doi.org/10.1002/cam4.4158
  2. Cancer of the Breast (Female) – Cancer Stat Facts. Chart Death Rate per 100,000 Persons by Race/Ethnicity: Female Breast Cancer. (2018). SEER. https://seer.cancer.gov/statfacts/html/breast.html

Support That Runs Deep: Pennsylvania Breast Cancer Coalition Funding to Wistar Has Been a Bridge to New Discoveries

Written by The Wistar Institute on . Posted in Featured News.

For almost 20 years, the Pennsylvania Breast Cancer Coalition (PBCC) has supported top Wistar researchers embarking on their scientific careers. For them, it has meant the opportunity to pursue scientific theories — no matter how off-the-beaten-track — and to investigate and make discoveries that could be transformative.

Wistar’s Dr. Zach Schug became the latest PBCC research grant winner. Funding has allowed him to study the complex role of acetate in cancer. He hopes to connect the dots between a high fat/high sugar diet, acetate metabolism, the gut microbiome, and gene expression to better understand how tumors eat, grow and progress in breast cancer.

PBCC founder Pat Halpin-Murphy and team came to Wistar for a heartfelt and socially distanced celebration and check presentation with Wistar’s president & CEO Dr. Dario Altieri and Dr. Schug.

“We are thrilled to focus our 2021 research grants funding on the treatments of tomorrow for patients with metastatic breast cancer,” said PBCC president and founder Pat Halpin-Murphy. “It is our hope that, with this research, scientists like Dr. Schug will find cures for patients whose disease has spread to advanced stages. Seeing these brilliant minds in action, and supporting their selfless work, is the motivation behind our mission of finding a cure for breast cancer now… so our daughters don’t have to.”

“We couldn’t do cutting-edge science without key funding from the PBCC, a local organization that has done so much for breast cancer research and care in our region,” said Dario Altieri, M.D., Wistar president and CEO, Cancer Center director and the Robert & Penny Fox Distinguished Professor. “We are fortunate to continue a long-standing partnership with the PBCC to advance the most innovative science and improve the lives of countless women with breast cancer.”

Out front of Wistar, the sun shone down on this special day, as the three discussed the shared opportunities and impact their organizations have made together.