While many American adults are trying to reduce cholesterol levels, certain cancerous tumors have a relentless appetite for the metabolite. Some tumor cells use as much cholesterol as they can access to accelerate their growth beyond the capabilities of normal cells.
Scientists at Sanford Burnham Prebys Medical Discovery Institute and their collaborators at the University of Illinois Chicago have published findings May 22, 2026, in Science Advances regarding a potential method for turning the table on these tumors by subverting their cholesterol cravings. The researchers revealed new insights into enzymes that help move cholesterol around cells. Without the help of these enzymes, a cholesterol traffic jam occurs, blocking the cancer cell's ability to fuel tumor growth.
Cancer cells with a mutation in the tumor-suppressing TP53 gene are known to produce extra cholesterol. This may make them more vulnerable to starvation if scientists can put a stop to the steady supply of the lipid.
"We need more ways to treat cancers with this common mutation," said Brooke Emerling, PhD, the director of and associate professor in the Cancer Metabolism and Microenvironment Program at the Sanford Burnham Prebys NCI-Designated Cancer Center. The TP53 gene is mutated in roughly half of all cancers.
"One of our main goals with this work was to find new treatment possibilities for the large subset of breast cancers harboring TP53 mutations," said Ryan Loughran, PhD '24, a postdoctoral associate in the Emerling lab. "We recognized a real opportunity in targeting the enzymes that control cholesterol transport, especially since cancer cells depend on this process far more than normal cells do."
Emerling and Loughran focus on difficult-to-treat forms of breast cancer, where TP53 mutations are found in more than 84% of triple-negative breast cancers and three of every four HER2-amplified breast cancers.
To better understand how to turn these cancers' cholesterol consumption into a weakness, the research team turned to a family of cell membrane lipids known as phosphoinositides and the kinase enzymes that regulate them. The investigators had shown that a branch of the lipid enzyme family known as phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks) were required for the growth of cancers with TP53 mutations in mice, and they suspected that this tumor prevention was due to the enzymes' role relocating cholesterol in the cell.
"Normally, when mice lose TP53 as the guardian of their genomes, they are fated to die from cancer in four-to-eight months," said Emerling. "When you delete these kinases, the animals are 100% protected and never develop a tumor-and cholesterol turned out to be one of the missing pieces in this puzzle."
The scientists conducted experiments in mouse and human cancer cells showing that PI5P4Ks influenced the movement and behavior of organelles that carry cholesterol around our cells. In cancer cells with TP53 mutations and PI5P4Ks, cholesterol-laden lysosomes were found near the exterior cell membrane. Without PI5P4Ks, lysosomes remained in the interior of the cells, near the nucleus.
Like with real estate, location is critical for lysosomes transporting cholesterol. While positioned near the edge of the cell, lysosomes and their cargo are in proximity with many receptor proteins, enzymes and signaling molecules that exist around the cell membrane. This includes mechanistic target of rapamycin complex 1 (mTORC1), an enzyme that governs cell growth and runs amok in cancer.
"When lysosome positioning is biased towards the cell nucleus, mTORC1 activation is suppressed," said Loughran. "This connects directly to our previous work, where we found that the loss of these kinases triggers starvation-like states in cancer cells.
"When PI5P4Ks are absent, the link between lysosomal cholesterol and mTORC1 is compromised, a bit like two ships passing in the night."
The change in lysosome position towards the cell's interior that occurs without PI5P4Ks reduced interaction with mTORC1 and prevented it from sending signals associated with tumor growth.
"The mTOR activation pathway is really what drives tumorigenesis, and so mTOR is an important target for cancer drug development," said Emerling. "If we can target mTOR activity in aggressive cancers by blocking the sensing of cholesterol, that would be a promising treatment strategy."
Previous research has looked at the use of statins as cancer drugs due to their ubiquity and safety as treatments for patients with high cholesterol. While more research is needed, studies so far suggest that tumors eventually acquire resistance to statins.
"It is important for us to find other ways to more comprehensively cut cancer cells off from cholesterol to impede their growth," said Loughran.
"We'll continue to explore blocking PI5P4Ks as a more targeted approach tailored to how tumors operate," said Emerling.
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