US researchers find cancer's secret weapon to defeat death

Yahoo

12 hours ago

Dallas (tca/dpa) — Fat isn't just a guilty pleasure — it's cancer's secret weapon. New research from UT Southwestern Medical Center is shedding light on why this is the case.
In a study published this month in the journal Nature, the researchers found cancer cells steal fat-packed molecules from the bloodstream, arming themselves with a potent antioxidant that shields them from death.
Tumours appear to do this by reeling in lipoproteins — molecules that carry fats and fat-soluble nutrients like vitamin E in the bloodstream — through sugar-coated molecules on their cell surface. These sulfated glycosaminoglycans (or GAGs) allow cancer cells to fortify their cell membranes with vitamin E and avoid a form of cell death called ferroptosis.
Though clinical applications are still a ways off, the study underscores how understanding cancer's metabolism could open new doors for treatment, said Dr. Shad Thaxton, an associate professor of urology at Northwestern University's Feinberg School of Medicine, who was not involved in the study.
'I think this paper and others in the field (emphasize) the appreciation for ferroptosis as a mechanism to kill cancer cells — that mechanism of cell death is so intimately intertwined with cell metabolism,' Thaxton said. 'I think what's interesting for people is that metabolism has a really big impact on the potential vulnerability of cancer cells to specific therapies.'
Building blocks with functional perks
Cancers rewire their metabolism in ways that support their growing horde of destructive cells. Some of this rewiring involves producing energy from glucose and acquiring cellular building blocks such as nucleic acids, proteins and lipids.
Amassing cellular building blocks is especially crucial since a tumour's uncontrolled growth lends to it creating a hostile microenvironment where there aren't enough nutrients and other resources, said Javier Garcia-Bermudez, an assistant professor at UT Southwestern Medical Center's Children's Medical Center Research Institute, who led the study.
Lipids are essential for a tumour to grow and progress. The plasma membrane of each cell is a bilayer of lipids; as cancer cells swell in number, they have to source lipids from their immediate environment or make their own to maintain their plasma membranes.
Garcia-Bermudez said that was the prevailing theory as to why lipids are so important to cancer. Emerging research has since discovered that lipids may offer cancer cells more functional perks. For example, a September 2024 study found that cancer cells use lipids called sphingolipids to go into stealth mode, evading detection and destruction by the immune system.
Studies have also found lipids are somehow involved in ferroptosis, a type of cell death discovered in 2012. A portmanteau of 'ferrous,' the Latin word for iron, and apoptosis, the scientific word for programmed cell death, ferroptosis happens when a buildup of toxic molecules called oxidants and iron overwhelms a cell, causing it to essentially rust from the inside out.
'Oxidants damage the lipids that are forming the membranes (of) a cell,' Garcia-Bermudez said. 'What's interesting is that cancer cells tend to produce more oxidants than normal cells,' he added, noting that there's been interest in understanding why some cancers are more susceptible to this type of damage and in using ferroptosis to kill cancer cells.
Cut the GAGs, kill the cancer
The crafty masters of survival that they are, cancer cells have devised ways to dodge ferroptosis. Unraveling the reason why put Garcia-Bermudez and his lab on a four-year journey of scientific inquiry.
One of the researchers' first findings, after screening 200 metabolic genes linked to cancer, was that an enzyme called glutathione peroxidase 4 was active in tumours. This wasn't a new discovery: Studies have shown this enzyme, which can stop lipids from degrading, plays a pivotal role in controlling ferroptosis.
When glutathione peroxidase 4 was erased from a cancer cell's genome, the tumor would die — unless it was given a drug blocking ferroptosis or fed lipoproteins.
'That was a clue that lipoproteins were somehow related to ferroptosis,' said Dr. Ralph DeBerardinis, director of UT Southwestern Medical Center's Eugene McDermott Center for Human Growth and Development, who coauthored the study.
In a battery of experiments that included depriving cancer cells in petri dishes of lipoproteins and exposing them to different antioxidants, the full picture began to be unveiled. Cancer cells were intercepting lipoproteins, particularly those bearing vitamin E — a fat-soluble antioxidant — from their surrounding environment. Like a fisherman with a fishing line, cancer cells accomplished this not with the usual reels used to catch lipoproteins but with long, flowy sugar chains called sulfated glycosaminoglycans (or GAGs). These molecules are attached to a cancer cell surface through another molecule called a proteoglycan.
When the scientists blocked the biochemical pathway responsible for manufacturing GAGs, this limited a lab-grown cancer cell's access to vitamin E and made it more vulnerable to ferroptosis. In mice grafted with cancer cells, cutting off the pathway slowed tumor growth.
The researchers also examined 20 tumours donated by patients with clear cell renal carcinoma, the most common type of kidney cancer, affecting over 640,000 people in the United States. These tumors had higher levels of GAGs and vitamin E — about 15 times more of the latter — compared to normal kidney tissue. Disrupting the biochemical pathway producing GAGs prevented kidney cancer cells from devouring vitamin E-laden lipoproteins, dying by the iron hand of ferroptosis.
Future research
Garcia-Bermudez and DeBerardinis caution that there is much more research to be done before their study's findings have any clinical application for treating cancer.
'We know that GAGS are on the surface, they speak to the lipoproteins and they affect the uptake of lipoproteins,' Garcia-Bermudez said. 'But how mechanistically this happens, especially in the cancer cell, hasn't been shown before … If we understand how this works and we find molecular targets that maybe we can treat with drugs and block, then we have a way to specifically deplete vitamin E in the tumor.'
DeBerardinis said the research does not suggest any association between dietary vitamin E and cancer risk, or how vitamin E levels correlate with cancer patient outcomes. Figuring out those possible connections would be points for future study.
In the short term, DeBerardinis said, these findings could be used to investigate whether tumours with higher levels of glycosaminoglycans or stored vitamin E are linked to patient outcomes, such as survival rates or how well they respond to treatment.
Thaxton said there are currently no federally approved cancer treatments that incite ferroptosis. His lab at Northwestern University's Feinberg School of Medicine is conducting research into synthetic lipoproteins devoid of any lipid passengers — a Trojan horse without soldiers hiding inside.
The cancer cells expect to get the lipoproteins with fats like cholesterol and vitamin E, Thaxton said, but 'they end up dying of ferroptosis. Our drug doesn't carry anything and it's through this mechanism by which you can kill the cell.'
For Garcia-Bermudez and DeBerardinis, their research efforts were like finding a needle in a haystack, one they hope to find more needles in.
'Our study is really exciting, but at the same time it's a very basic discovery,' Garcia-Bermudez said. 'It was incredible to discover something that people have not observed in cancer before, to understand why these tumours are so resistant. I'm super excited to keep working on this.'