Hoxhaj awarded Vilcek Prize for ‘Creative Promise in Biomedical Science’

Photo courtesy of Vilcek Foundation

Gerta Hoxhaj, Ph.D., has been awarded the 2024 Vilcek Prize for ‘Creative Promise in Biomedical Science.’ The Vilcek Foundation annually recognizes immigrant professionals in biomedical sciences, in addition to arts and humanities, who have demonstrated outstanding achievements early in their careers. The award includes a $50,000 cash prize.

Dr. Hoxhaj, who was born and raised in Albania, is an Assistant Professor at Children’s Medical Center Research Institute (CRI) at UT Southwestern and Director of CRI’s Hoxhaj lab, where she studies cancer metabolism.

Read more about Dr. Hoxhaj’s Vilcek Prize.


Video courtesy of the Vilcek Foundation.

DeBerardinis named NCI ‘2023 Outstanding Investigator’

Ralph DeBerardinis, M.D., Ph.D., is one of 17 cancer researchers across the country honored with the National Cancer Institute’s ‘2023 Outstanding Investigator Award,’ in recognition of his lab’s contributions toward breakthroughs in cancer research.

For the next 7 years, Dr. DeBerardinis will receive $600,000 annually, “allowing substantial time for funded investigators to take greater risks and be more adventurous in their research,” according to the NCI.

Dr. DeBerardinis is a Howard Hughes Medical Institute Investigator, Professor at Children’s Medical Center Research Institute at UT Southwestern (CRI), and Director of CRI’s Genetic and Metabolic Disease Program. The DeBerardinis lab studies how oncogenic control of metabolism supports tumor progression. Dr. DeBerardinis also studies pediatric inborn errors of metabolism, using metabolomics and genomics to identify new disease genes and deepen understanding of metabolism’s role in human health. One goal of the Outstanding Investigator Award will be to use inborn errors of metabolism as a window into mechanisms of cancer initiation.

Read more about Dr. DeBerardinis’ NCI award.

Edward Owusu Kwarteng Awarded Minority Hematology Fellow Award from ASH

Edward Owusu Kwarteng’s, Ph.D., interest in hematological research began while volunteering at a medical diagnostic lab in his home country of Ghana. There, he saw firsthand how disorders like sickle cell disease, anemia, and hematologic cancers affected the lives of others. This experience motivated him to pursue a scientific career in hematology. Since then, Dr. Owusu Kwarteng has worked and studied in four countries across three continents to pursue his goal, including CRI, where he currently works as a postdoctoral fellow in the Agathocleous lab.

His research efforts were recently recognized with a highly competitive Minority Hematology Fellow Award from the American Society of Hematology (ASH). This award encourages early-career researchers from historically underrepresented minority groups in the U.S. and Canada to pursue a career in academic hematology. As part of this grant, he will receive $100,000 over a two- to three-year period to study the metabolism of hematopoietic stem cells (HSC). Through the program, he’ll also be offered mentorship from members of ASH, the Center for International Blood and Marrow Transplant Research, and the American Society for Transplantation and Cellular Therapy.

“ASH is a prestigious organization, and I’m honored to have been selected,” said Dr. Owusu Kwarteng. “Receiving an award from them highlights the importance of my research focus and will give me protected time to thoroughly investigate glucose metabolism in HSCs and other hematopoietic cells. I aspire to open my own lab after completing my postdoctoral fellowship, and the training I’ll receive in this program will be instrumental in helping me achieve this.”

Michalis Agathocleous, Ph.D., an Assistant Professor in CRI and Dr. Owusu Kwarteng’s mentor, said, “Edward is an incredibly motivated and committed scientist. I believe his proposed work will have far-reaching implications for both the hematopoiesis and metabolism fields.”

Ultimately, Dr. Owusu Kwarteng hopes to find or contribute to treatments of sickle cell anemia and other anemias arising from hematological disorders and infection.

Divya Bezwada Receives the 2023 STAT Wunderkind Award

Divya Bezwada, Ph.D.

Divya Bezwada, Ph.D., a former graduate student in the DeBerardinis lab in Children’s Medical Center Research Institute at UT Southwestern (CRI), has been named a 2023 STAT Wunderkind for her work in cancer metabolism. This annual award celebrates early-career scientists and clinicians making groundbreaking discoveries in health and medicine. Dr. Bezwada was selected from among hundreds of nominees across North America.

“I am honored to receive this award. The discoveries we made would not have been possible without the teams I worked with in the lab and clinic, and the patients who generously participated in research-focused clinical trials,” said Dr. Bezwada. “I am grateful to everyone involved, especially my mentor, Ralph DeBerardinis, who gave me the freedom to explore as a graduate student.”

During her time at CRI, Dr. Bezwada made several discoveries related to the metabolism of clear cell renal cell carcinoma (ccRCC)— the most common type of kidney cancer in patients. ccRCC cells are known to have disordered metabolic activities in culture, but Dr. Bezwada’s work is the first to assess metabolic activities directly in human ccRCC. She discovered how these tumors use different fuels to support their growth in patients, and uncovered differences in fuel utilization before and after these tumors metastasize. While ccRCCs growing in the kidney suppress fuel oxidation in the mitochondria, this pathway is re-activated in tumors that metastasize. Dr. Bezwada’s unexpected findings may lead to new ways to prevent ccRCC metastasis, or treat tumors that have already metastasized.

“I cannot think of a more deserving student for the STAT Wunderkind Award,” said Ralph DeBerardinis, M.D., Ph.D., a Professor at CRI and Dr. Bezwada’s mentor. “She is an exceptional scientist and has made important contributions to the field of cancer metabolism. Her work has given rise to a whole series of questions we will try to answer in the coming years.”

Dr. Bezwada, who graduated in May with a Ph.D., will continue her work in cancer biology as a postdoctoral fellow in the lab of Benjamin Cravatt, Ph.D., at Scripps Research in La Jolla, California.

Comprehensive isotopomer analysis of glutamate and aspartate in small tissue samples

Stable isotopes are powerful tools to assess metabolism. 13C labeling is detected using nuclear magnetic resonance (NMR) spectroscopy or mass spectrometry (MS). MS has excellent sensitivity but generally cannot discriminate among different 13C positions (isotopomers), whereas NMR is less sensitive but reports some isotopomers. Here, we develop an MS method that reports all 16 aspartate and 32 glutamate isotopomers while requiring less than 1% of the sample used for NMR. This method discriminates between pathways that result in the same number of 13C labels in aspartate and glutamate, providing enhanced specificity over conventional MS. We demonstrate regional metabolic heterogeneity within human tumors, document the impact of fumarate hydratase (FH) deficiency in human renal cancers, and investigate the contributions of tricarboxylic acid (TCA) cycle turnover and CO2 recycling to isotope labeling in vivo. This method can accompany NMR or standard MS to provide outstanding sensitivity in isotope-labeling experiments, particularly in vivo.

Read the full article in Cell Metabolism. 

Adiponectin receptors sustain haematopoietic stem cells throughout adulthood by protecting them from inflammation

How are haematopoietic stem cells (HSCs) protected from inflammation, which increases with age and can deplete HSCs? Adiponectin, an anti-inflammatory factor that is not required for HSC function or haematopoiesis, promotes stem/progenitor cell proliferation after bacterial infection and myeloablation. Adiponectin binds two receptors, AdipoR1 and AdipoR2, which have ceramidase activity that increases upon adiponectin binding. Here we found that adiponectin receptors are non-cell-autonomously required in haematopoietic cells to promote HSC quiescence and self-renewal. Adiponectin receptor signalling suppresses inflammatory cytokine expression by myeloid cells and T cells, including interferon-γ and tumour necrosis factor. Without adiponectin receptors, the levels of these factors increase, chronically activating HSCs, reducing their self-renewal potential and depleting them during ageing. Pathogen infection accelerates this loss of HSC self-renewal potential. Blocking interferon-γ or tumour necrosis factor signalling partially rescues these effects. Adiponectin receptors are thus required in immune cells to sustain HSC quiescence and to prevent premature HSC depletion by reducing inflammation.

Read the full article in Nature Cell Biology. 

CRI’s Sean Morrison elected to European Molecular Biology Organization

Dr. Morrison holds the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research at Children’s Research Institute at UT Southwestern and the Mary McDermott Cook Chair in Pediatric Genetics

DALLAS – July 4, 2023 – Stem cell biologist Sean J. Morrison, Ph.D., Howard Hughes Medical Institute Investigator and founding Director and Professor of the Children’s Medical Center Research Institute at UT Southwestern (CRI), has been elected by his peers as an associate member of the European Molecular Biology Organization (EMBO).

Dr. Morrison studies the cellular and molecular mechanisms that regulate stem cell function and the role these mechanisms play in cancer. His laboratory pioneered methods to purify stem cells from multiple tissues and discovered mechanisms that allow stem cells to persist throughout life to regenerate tissues after injury. His laboratory discovered key mechanisms that regulate stem cell self-renewal as well as the location and cellular composition of specialized microenvironments that promote the maintenance of hematopoietic stem cells in adult blood-forming tissues.

Fiona Watt, EMBO Director, said of the newly elected members who reside in more than 20 countries “These remarkable scientists have unraveled molecular secrets of life, deepened our understanding of health and disease, and are paving the way for further discoveries and innovations. Their achievements reinforce the critical role that life science research plays in the lives of citizens across Europe and the world.”

Dr. Morrison, one of 26 members of the U.S. National Academy of Sciences and 19 members of the U.S. National Academy of Medicine at UT Southwestern Medical Center, joins the EMBO community of more than 2,000 leading life science experts, including 91 Nobel laureates who have been elected to EMBO Membership. New EMBO members are elected by existing EMBO members. The new members will be formally welcomed to EMBO at the annual Members’ Meeting in Heidelberg, Germany, between 25-27 October 2023.

The Morrison Lab studies the intrinsic and extrinsic mechanisms that regulate stem cell self-renewal and the role these mechanisms play in cancer. Self-renewal is the process by which stem cells divide to make more stem cells, perpetuating stem cells throughout life to regenerate tissues.

Dr. Morrison’s team discovered a series of key regulators that distinguish stem cell self-renewal from the proliferation of restricted progenitors in the same tissues. He also identified ways in which self-renewal mechanisms change with age, conferring temporal changes in stem cell properties that match the changing growth and regeneration demands of tissues.

In terms of cell-extrinsic mechanisms, Dr. Morrison identified the location and cellular composition of hematopoietic stem cell (HSC) niches in adult bone marrow and spleen and discovered the Leptin Receptor+ perivascular stromal cells that are the major source of factors required for HSC maintenance in the bone marrow. Researchers demonstrated that HSCs are metabolically distinct from restricted progenitors in vivo and depend upon metabolic regulation for epigenetic control and leukemia suppression.

His lab further discovered that distant metastasis by melanoma cells is limited by oxidative stress and that successfully metastasizing melanoma cells undergo reversible metabolic changes to cope with oxidative stress. They are working to test if “pro-oxidant” therapies that exacerbate oxidative stress in cancer cells can be used to inhibit cancer progression.

Dr. Morrison served as the president of the International Society for Stem Cell Research (2015-2016) and has been active in public policy issues surrounding stem cell research. He is also a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research and a member of the Harold C. Simmons Comprehensive Cancer Center. Dr. Morrison holds the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research at CRI and the Mary McDermott Cook Chair in Pediatric Genetics. Born in Halifax, Nova Scotia, Dr. Morrison completed a B.Sc. in biology and chemistry at Dalhousie University in 1991, a Ph.D. in immunology at Stanford University in 1996, and a postdoctoral fellowship in neurobiology at Caltech in 1999.

About CRI

Children’s Medical Center Research Institute at UT Southwestern (CRI) is a joint venture of UT Southwestern Medical Center and Children’s Medical Center Dallas, the flagship hospital of Children’s Health. CRI’s mission is to perform transformative biomedical research to better understand the biological basis of disease. Located in Dallas, Texas, CRI is home to interdisciplinary groups of scientists and physicians pursuing research at the interface of regenerative medicine, cancer biology and metabolism. For more information, visit: cri.utsw.edu. To support CRI, visit: give.childrens.com/about-us/why-help/cri/.

Hoxhaj receives Pew Charitable Trusts research award

Gerta Hoxhaj, Ph.D., Assistant Professor

Dallas, TX – June 15, 2023 – UT Southwestern faculty member, Gerta Hoxhaj, Ph.D., Assistant Professor at the Children’s Medical Center Research Institute at UT Southwestern (CRI) and of Pediatrics and Biochemistry, has been selected for prestigious Pew Charitable Trusts biomedical research program.

The Pew Charitable Trusts and The Alexander and Margaret Stewart Trust chose Dr. Hoxhaj as a Pew-Stewart Scholar for Cancer Research. Now in its 10th year, the national initiative supports promising early-career scientists whose research will accelerate discovery and advance progress toward a cure for cancer. Dr. Hoxhaj is among five scholars recognized for their tremendous potential to solve some of cancer’s greatest challenges. She will receive a four-year grant of $300,000

“I am incredibly honored and humbled to be selected as a Pew-Stewart Scholar,” said Dr. Hoxhaj, who is also a Cancer Prevention and Research Institute of Texas Scholar and a member of UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center. “This award recognizes the creativity and hard work of my laboratory, where we continually strive to make important contributions to our field.”

Dr. Hoxhaj’s lab studies metabolism, which she describes as a complex web of thousands of chemical reactions that generate energy to support life. A major focus in her lab is uncovering the biological roles and regulation of a molecule called NADPH.

“By donating electrons, NADPH charges a battery of biochemical reactions that protect cells from oxidative damage and facilitates their growth and survival. However, dysregulation of NADPH metabolism has been linked to several human diseases, including cancer, metabolic disorders, and neurodegeneration,” she said.

Dr. Hoxhaj’s lab is developing new biochemical and genetic approaches that allow the study of NADPH molecules in specific cellular compartments, tissues, and cancer types.

“Our ultimate goal is to gain a complete understanding of NADPH metabolism and harness this knowledge to develop new strategies to combat cancer and treat disease,” she said.

Dr. Hoxhaj received her bachelor’s degree from Bogazici University in Istanbul, Turkey, with a double major in molecular biology and genetics and chemistry. She earned her Ph.D. in biochemistry and cell signaling from the MRC Protein Phosphorylation and Ubiquitylation Unit at the University of Dundee in Scotland. She joined UTSW in 2019.

Divya Bezwada wins Nominata Award

“Divya Bezwada’s discoveries in human kidney cancer have changed the way we think about how these tumors grow and metastasize, and they give rise to a whole series of questions we will try to answer in the coming years,” said the recent graduate’s mentor, Ralph DeBerardinis, M.D., Ph.D., Professor in the Children’s Medical Center Research Institute at UT Southwestern.

For this work, Divya Bezwada, Ph.D., is the 2023 winner of the Nominata Award, the highest honor bestowed on a student by the UT Southwestern Graduate School of Biomedical Sciences.

It’s remarkable success on an unexpected path. As a college student interested in attending medical school, Dr. Bezwada initially regarded a laboratory as a place to do predesigned work with unsurprising results. Then, in the final semester of her senior year, a professor steered her toward a research lab.

“He saw that I liked discovery,” she said. “It was my first time in a lab where it wasn’t just to check off a required box – it was to really learn something new.”

That spirit has carried her through graduate school and research at UT Southwestern, where she has identified metabolic changes in tumor cells from kidney cancer patients.

“Divya’s project required an exceptional level of creativity, determination, and collaboration,” said Dr. DeBerardinis, also Chief of the Division of Pediatric Genetics and Metabolism, Professor of Pediatrics at UT Southwestern, and a member of the Harold C. Simmons Comprehensive Cancer Center.

This is her second major recognition from the Graduate School; in 2020, she received the Ida M. Green Award for her outstanding commitment to the well-being of fellow students, exceptional community service, and research excellence.

Dr. Bezwada, who graduated in May with a Ph.D. in cancer biology, investigated how kidney tumors use different nutrients to support their growth and survival. The key to tracking the cells’ function was carbon-13 (13C), a form of carbon that’s heavier than the most common type, carbon-12 (12C).

By making nutrients that contain 13C instead of 12C, she could infer how the cell is working by measuring which products of metabolism contain 13C. (For instance, 13C-labeled citrate indicated normal mitochondrial metabolism, while 13C-labeled lactic acid produced in the presence of oxygen showed that glucose is being consumed less efficiently in the cell’s body.)

Dr. Bezwada’s research focused on clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer. ccRCC cells are known to have a disordered metabolism in culture, but her work is the first to identify how ccRCC tumors use different fuels to support growth in humans.

In close collaboration with her clinical mentor, Professor of Urology Vitaly Margulis, M.D., and Urology surgical teams, Dr. Bezwada administered these labeled nutrients to patients who were having surgery to remove kidney tumors. Once the tumors were removed, she froze tissue for analysis and analyzed fresh tissue for oxygen usage, 13C enrichments, and other factors.

The surgery time is long enough for the tumor to pick up the 13C-labeled molecules and metabolize them into 13C-labeled products of metabolism, which Dr. Bezwada could detect through a technique called mass spectrometry. The findings showed that ccRCC tumors suppress a step in mitochondrial glucose oxidation called the TCA cycle. This difference in energy generation in tumors was first described by German scientist Otto Warburg in the 1920s.

Dr. Bezwada’s work marks “the first definitive demonstration of the Warburg effect … in human tumors,” said Andrew Zinn, M.D., Ph.D., Dean of the Graduate School.

She also developed techniques to culture fresh patient tissues and demonstrated that tumor tissues retain their metabolic characteristics outside of the body, indicating that ccRCC tumor metabolism was intrinsic to the tumor.

However, Dr. Bezwada found something surprising when studying ccRCC tumors that had spread to other organs. The metastatic tumors used more glucose in the TCA cycle than primary ccRCCs. This difference in metabolism might be exploitable in preventing or treating cancer spread.

“That’s really the ultimate goal – finding effective therapies for metastatic kidney cancer patients – but we’re well out from that,” she said. “We’re still in the early days of figuring out what causes this difference during metastasis and what’s the critical driver. But our work is an important first step.”

After graduation, Dr. Bezwada will continue her work in cancer and chemical biology as a postdoctoral fellow in the lab of Benjamin Cravatt, Ph.D., at Scripps Research in La Jolla, California.

The metabolism of neutrophils and its contribution to severe COVID-19

Blue stains indicate the nuclei of live neutrophils. The green ballooning structures show NET formation after GAPDH inhibition.

Metabolic changes in neutrophils, the most abundant type of white blood cell, may contribute to severe COVID-19, according to scientists at Children’s Medical Center Research Institute at UT Southwestern (CRI).

Severe COVID-19 is caused by dysfunction of the immune system in response to SARS-CoV-2 infection. It has been speculated that the metabolism of immune cells could contribute to this dysfunction. However, no one had analyzed the levels of metabolites, the small molecules produced during metabolism, in immune cells from patients. In the study, published in Nature Communications, Yafeng Li, Ph.D., Michalis Agathocleous, Ph.D., and colleagues performed metabolomics analysis of neutrophils isolated from patients with severe or mild COVID-19 and from healthy individuals to understand metabolic changes in severe disease. Researchers identified changes in several metabolic pathways in the cells of severe COVID-19 patients, including pathways not previously implicated in COVID-19 or other inflammatory diseases.

One of these changes was inhibition of a key metabolic enzyme called GAPDH. Scientists in the Agathocleous lab found GAPDH inhibition caused the formation of neutrophil extracellular traps (NETs)— unique structures produced by neutrophils. NETs are essential for containing pathogens but can also damage tissues when responding to many inflammatory diseases, including sepsis, malaria, and stroke, in addition to severe COVID-19.

“Inhibiting GAPDH induced many changes inside neutrophils, including blocking ATP production – the main energy-carrying molecule within cells. Surprisingly, it was not the loss of ATP that caused NET formation; rather, GAPDH controlled NET formation by influencing the cellular pH,” said Dr. Li, an Assistant Instructor at CRI. 

According to researchers, the discovery of GAPDH as an innate NET suppressor suggests that preserving GAPDH activity or pH balance in neutrophils could reduce pathology in inflammatory diseases.

“This study provides a first look at the metabolic composition of immune cells in COVID-19. It also suggests that pathological immune cell metabolism contributes to disease severity, provides a resource to understand the metabolism of neutrophils, and opens a new direction to investigate how metabolism affects neutrophil survival and function,” said Dr. Agathocleous, Assistant Professor at CRI, and supervisor of the study. 

Dr. Li added, “Our work will stimulate rethinking the role of glycolysis in the hematopoietic and immune systems. This work started with samples from COVID-19 patients, but its implications extend beyond that to understanding the control of NET formation and the metabolic functions of GAPDH.” 

Dr. Agathocleous is a Cancer Prevention and Research Institute of Texas (CPRIT) scholar and an American Society of Hematology faculty scholar. This work was supported by CPRIT (RR180007), the American Society of Hematology Faculty Scholar Award, the Welch Foundation (I-2053-20210327), the Moody Foundation, and the National Institutes of Health (R01DK125713 and R01HL161387). Patient samples were collected by the UT Southwestern SARS-CoV-2 Biorepository.