The finding that a rare tumor type of cancer is unable to synthesize cholesterol, and is therefore dependent on environmental cholesterol, opens the door to an entirely new way of approaching treatment.

The work published this week in Nature, in a paper titled “Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death,” was done in the lab of Kıvanç Birsoy, PhD, an assistant professor at The Rockefeller University.

Birsoy has long been fascinated by the fact that, in rare cases, cancers lose the ability to make key nutrients. Some types of leukemia, for example, are unable to synthesize the amino acid asparagine. As a first line of defense against these cancers, doctors give patients a drug known as asparaginase, which breaks down the amino acid, removing it from the blood. Without access to external stores of the nutrient, the cancer cells die.

Cholesterol is essential for cells to grow and proliferate. The team, led by Javier Garcia-Bermudez, PhD, a postdoctoral fellow at The Rockefeller University, used a competitive proliferation assay on a pooled collection of DNA-barcoded cell lines to identify a subset of cancer cells that is auxotrophic for cholesterol and thus highly dependent on its uptake. The researchers placed 28 different cancer cell types in an environment that lacked cholesterol, and noted which ones survived.

Cells associated with a rare type of lymphoma, known as ALK+ anaplastic large cell lymphoma (ALCL), did not survive in these conditions, suggesting that these cells could not synthesize cholesterol on their own. “These cells become dependent on taking up cholesterol from their environment, and we can use this dependency to design therapies that block cholesterol uptake,” said Birsov.

Through analyzing gene expression data, the researchers then pinpointed the loss of a particular enzyme, squalene monooxygenase, as a cause of cholesterol auxotrophy, particularly in ALK+ ALCL cell lines and primary tumors. “Squalene monooxygenase catalyzes the oxidation of squalene to 2,3-oxidosqualene in the cholesterol synthesis pathway and its loss results in accumulation of the upstream metabolite squalene, which is normally undetectable. In ALK+ ALCLs, squalene alters the cellular lipid profile and protects cancer cells from ferroptotic cell death, providing a growth advantage under conditions of oxidative stress and in tumor xenografts,” the authors wrote.

Though the inability to make cholesterol should be a bad thing, a buildup of squalene, Birsoy noted, may actually be beneficial to cancer cells. “These cells need to deal with oxidative stress in their environment. And we believe squalene is one way to increase antioxidant capacity,” he said.

A CRISPR-based genetic screen identified cholesterol uptake by the low-density lipoprotein receptor as essential for the growth of ALCL cells in culture and as patient-derived xenografts. The researchers knocked out the cancer cells’ LDL receptors, a primary means of absorbing external cholesterol. As a result, the cells had no access to the nutrient and died. This outcome points to a novel way to kill ALCL cells, which can become resistant to chemotherapy. “We think therapies that block uptake of cholesterol might be particularly effective against drug-resistant forms of ALCL,” said Birsoy.

“This work reveals that the cholesterol auxotrophy of ALCLs is a targetable liability and, more broadly, that systematic approaches can be used to identify nutrient dependencies unique to individual cancer types,” the authors wrote. Moving forward, the researchers plan to screen other cancers for similar vulnerabilities. “This is part of a larger strategy of looking for nutrient dependencies or deficiencies in various cancer types,” Birsoy noted.



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