Researchers include (l-r) co-first author Lingjie Sang, Ph.D., postdoctoral fellow; senior author Javier Garcia-Bermudez, Ph.D., Assistant Professor in Children’s Medical Center Research Institute at UT Southwestern and Pediatrics; and co-first author Dylan Calhoon, B.S., graduate student researcher. Credit: UT Southwestern Medical Center

Scientists have discovered tumors can tap a nontraditional pathway to acquire lipoproteins—molecules that transport fat in blood—which enriches cancer cells with an antioxidant shield to survive stress, according to new research from Children's Medical Center Research Institute at UT Southwestern (CRI) published in Nature.

Javier Garcia-Bermudez, Ph.D., Assistant Professor in CRI and Pediatrics, along with first authors from his lab, Dylan Calhoon, B.S., graduate student researcher, and Lingjie Sang, Ph.D., postdoctoral fellow, found cancer cells don't rely on usual receptors to acquire lipoproteins. Instead, tumors use a different mechanism: special sugar-coated structures on the cell surface called sulfated glycosaminoglycans (GAGs).

Cancer cells need a steady supply of lipids to build their membranes, support vital functions, and survive stresses associated with disease progression. Cells can obtain lipids in two ways: making them from scratch or acquiring them from the blood via lipoproteins.

Lipoproteins transport the majority of lipids in blood, including a lipid called α-tocopherol—a form of vitamin E that cells cannot make on their own and can only be obtained from dietary intake. While α-tocopherol is an antioxidant that can nourish healthy tissues, Dr. Garcia-Bermudez and his team found this potent antioxidant shield is used by cancer cells to resist ferroptosis, a type of cell death triggered by toxic lipid by-product buildup.

CRI scientists showed that blocking GAG production in tumors reduced lipoprotein uptake and vitamin E levels, slowed tumor growth, and made cancer cells more vulnerable to elimination by ferroptosis.

"By targeting GAGs in cancer, we may have uncovered a way to strip tumors of their antioxidant shield provided by vitamin E, making them more vulnerable to therapies that trigger oxidative stress to kill cancer cells, " Dr. Garcia-Bermudez said.

"GAGs also give tumors a unique way to access lipoproteins, as compared to how most healthy tissues acquire lipids. We also found this pathway can be exploited in human tumors, which we hope will lead to future cancer treatments with fewer side effects."

To understand the impact in humans, Dr. Garcia-Bermudez collaborated with UTSW researchers studying clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, as part of the Kidney Cancer Program (KCP) in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

By studying 20 patient kidney tumors, scientists confirmed that cancer cells had higher levels of GAGs and vitamin E compared to normal kidney tissue. When researchers then disrupted GAG production, patient-derived ccRCC tumors became less aggressive.

"These findings suggest that antioxidants are important for ccRCC to thrive and that interfering with their uptake may be beneficial and interrupt tumor progression. Furthermore, by identifying the uptake mechanism, Dr. Garcia-Bermudez provides a target for possible therapeutic intervention, " said James Brugarolas, M.D., Ph.D., founding Director of the KCP and Professor of Internal Medicine.

Future research in the Garcia-Bermudez Lab will focus on developing pharmacological approaches to precisely target GAGs and explore whether other lipids carried by lipoproteins—beyond vitamin E—help tumors spread or resist treatment.

More information: Dylan Calhoon et al, Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis, Nature (2025). DOI: 10.1038/s41586-025-09162-0  Journal information: Nature