Nathaniel Snyder, assistant professor in the Aging + Cardiovascular Discovery Center in the Department of Cardiovascular Sciences at the Lewis Katz School of Medicine, served as one of the principal investigators on the study, which was published online May 27 in the scientific journal Nature.
Nathaniel Snyder, assistant professor in the Aging + Cardiovascular Discovery Center in the Department of Cardiovascular Sciences at the Lewis Katz School of Medicine, is one of the senior investigators on a new study that reveals how ovarian cancer cells use a nutrient-related process involving carnitine production to maintain the DNA repair machinery they need to continue growing.
Photo by Ryan S. Brandenberg
A previously unrecognized metabolic pathway helps aggressive ovarian cancer cells repair DNA damage and survive treatment, according to new research from Temple University’s Lewis Katz School of Medicine. The discovery could open the door to new therapeutic strategies.
The study, published online May 27 in the scientific journal Nature, reveals how ovarian cancer cells use a nutrient-related process involving carnitine production to maintain the DNA repair machinery they need to continue growing. Disrupting this process weakens cancer cells’ ability to repair DNA damage and increases their sensitivity to treatment.
“This work uncovers a completely unexpected connection between cellular metabolism and DNA repair,” said Nathaniel Snyder, assistant professor in the Aging + Cardiovascular Discovery Center in the Department of Cardiovascular Sciences at the Katz School and one of the study’s senior investigators. “We found that ovarian cancer cells rely on a pathway tied to carnitine synthesis to maintain effective DNA repair.”
The findings are particularly important for high-grade serous carcinoma, the deadliest form of ovarian cancer and one that is frequently diagnosed at an advanced stage. Although treatments such as chemotherapy and PARP inhibitors can initially be effective, many tumors eventually develop resistance.
Researchers increasingly recognize that cancer metabolism plays a major role in treatment response. The team, a close collaboration between Temple and Katherine Aird’s laboratory at The Wistar Institute, focused on alpha-ketoglutarate (αKG), a molecule central to metabolism. Previous work has shown that cancer cells can depend on αKG for growth and survival, but its role in DNA repair was unclear.
Using ovarian cancer cells, animal models and analyses of patient tumor samples, Snyder and colleagues investigated how αKG influences homologous recombination, a major DNA repair pathway cancer cells use to survive treatment-induced damage.
The team discovered that αKG supports carnitine production via the enzyme TMLHE. Carnitine is typically recognized for its role in transporting fatty acids for energy production, but the researchers found it also helps maintain nuclear acetyl-coenzyme A (CoA) levels and histone acetylation—molecular modifications that regulate access to DNA and enable efficient repair of double-strand DNA breaks.
“When we blocked this pathway, the cancer cells lost key histone acetylation marks and became much less capable of repairing DNA damage,” Snyder said. “That makes them significantly more vulnerable to therapies that rely on overwhelming cancer cells with DNA injury.”
The researchers showed that inhibiting IDH1, an enzyme involved in generating αKG, reduced histone acetylation and hindered DNA repair in ovarian cancer cells. Similar effects occurred when the team suppressed TMLHE, confirming that carnitine synthesis within cells plays a critical role in maintaining repair capacity. Importantly, restoring carnitine or acetylcarnitine, a direct precursor of acetyl-CoA in the cell nucleus, reversed many of these effects.
The new study also highlights the clinical relevance of αKG-mediated carnitine synthesis. Analyses of ovarian cancer patient samples show that elevated TMLHE expression correlates with increased histone acetylation and shorter time before disease progression. Higher serum acetylcarnitine levels were likewise associated with poorer outcomes.
These observations suggest that αKG-mediated carnitine synthesis may not only drive tumor survival but could also serve as a biomarker for more aggressive disease, raising the possibility of identifying patients who might benefit most from therapies targeting the metabolic vulnerability.
Although additional research and clinical testing will be necessary, the study’s findings provide a strong foundation for exploring metabolism-based treatment combinations in ovarian cancer and potentially other malignancies.
“Cancer cells are remarkably adaptable,” Snyder explained. “What this study shows is that they can rewire metabolism in ways we didn’t fully appreciate to preserve critical survival functions. Understanding those adaptations gives us entirely new opportunities to intervene, including through nutrition, since carnitine is very modifiable by diet.”
The researchers plan next to investigate the effects of existing drugs on carnitine, as well as the role of carnitine synthesis in other cancers. Blood cancers are of special interest, since several are known to carry mutations that can alter αKG.
“The ultimate goal is to translate these mechanistic discoveries into strategies that can genuinely help patients,” Snyder said. “By exposing the metabolic dependencies cancer cells rely on, we move closer to developing treatments that are both more precise and more effective.”
Other researchers who contributed to the new study include co-corresponding author Katherine Aird, first author Apoorva Uboveja, Baixue Yang, Raquel Buj, Amandine Amalric, Aidan R. Cole and Miho Naruse, The Wistar Institute; Julie A. Disharoon and David T. Long, Medical University of South Carolina; Hui Wang, Naveen Kumar Tangudu, Richard S. Fang, Evan Levasseur, Zhentai Huang, Frank P. Vendetti, Jeff Danielson, Esther Elishaev, Kristine Cooper, Nadine Hempel, Wayne Stallaert and Christopher J. Bakkenist, University of Pittsburgh School of Medicine; Emily Megill, Daniel S. Kantner, Adam Chatoff, Hafsah Ahmad, Mariola M. Marcinkiewicz, Jennifer L. Pennise, Alison Jaccard and Andrea Andress Huacachino, Lewis Katz School of Medicine at Temple University; Sarah Graff, Ellen De Pieri, and Simone Sidoli, Albert Einstein College of Medicine; Erika S. Dahl, Penn State College of Medicine; Lauren Borho and Francesmary Modugno, Magee-Womens Research Institute, University of Pittsburgh School of Medicine; Miriam D. Post and Benjamin G. Bitler, University of Colorado Anschutz Medical Campus; and Kathryn E. Wellen, University of Pennsylvania.
The research was supported by funding from the National Institutes of Health, the American Cancer Society, the Sandy Rollman Ovarian Cancer Foundation, the Ovarian Cancer Research Alliance, the Congressionally Directed Medical Research Program, the HERA Ovarian Cancer Foundation, the Melanoma Research Foundation, the Janet Burroughs Ovarian Cancer Foundation, the Hollings Cancer Center Abney Graduate Fellowship, the Hevolution Foundation, the Einstein-Mount Sinai Diabetes Center, the UPMC Hillman Cancer Center and The Wistar Institute.
