Cancer cells rarely start out stealthily. On the contrary, they alert the immune system to their presence by displaying chemical red flags on their membranes. When detected, the body’s defense system can attack and destroy the rebel cells before they can cause significant damage. Lipids, fatty molecules traditionally thought of as the fuel supply for tumor growth, are at the center of this early detection system.
However, a new study published in Nature shows that a specific lipid type is essential for cancer immune evasion – so much so that some cancer cells cannot reproduce without it. The findings validate long-standing beliefs that not only is this lipid a key factor in cancer biology (and thus a key therapeutic target).
“The cancer cells are changing the way they metabolize this lipid, which in turn distorts the ‘eat me’ signals,” says first author Mariluz Soula, a former graduate student in Kıvanc Birsoy’s lab and now a scientist at Lyme Therapeutics. “This paints a very different picture of the role of lipids in cancer development.”
Scientists have long known that cancer cells alter lipid metabolism, but it was generally believed that cancer cells gobble up these lipids for energy — consuming the fatty molecules to help tumors grow and spread far beyond healthy cells.
“We knew from the literature that increased lipid levels are related to the severity of cancer growth and metastasis, but it was not clear how,” says Soula. The Birsoy lab, together with the lab of Gabriel D. Victoria, tried to answer this question by investigating the genes involved in this process. They then transplanted a series of cancer cells, each missing a different gene, into mice with and without immune systems – thereby revealing which lipids the cancer could not survive without.
The result: so-called “sphingolipids.” Sphingolipids, discovered by German chemist Johann Ludwig Wilhelm Thudichum in the late 1800s, were named after the mysterious Sphinx of Greek folklore because their structure and function were mysterious. Two centuries later, sphingolipids remain less of a mystery. “We know that sphingolipids are not actually used for energy,” says Soula. “They’re mainly in cell membranes to form scaffolding for signaling proteins.”
This discovery raised an interesting possibility. Was lipid metabolism in cancer cells really a story of hungry cells consuming more energy? Or was it a key part of the cancer cell’s efforts to subtly manipulate cell signaling and trick the immune system?
To investigate how sphingolipids were promoting cancer growth, the team used an FDA-approved drug that is used to treat Gaucher disease – a genetic disorder in which the ability to break down lipids is reduced. The drug essentially blocks glycosphingolipid synthesis, and the team found that it inhibited tumor growth in pancreatic, lung and colorectal cancer models.
They also found that depletion of glycosphingolipids prevented the formation of “lipid nanodomains,” which assemble signaling molecules together on membranes, thereby affecting cell surface receptors on the cell surface in such a way that they become more vulnerable to immune responses. These findings suggest that cancer cells accumulate glycosphingolipids to obscure inflammatory signals, and that inhibiting glycosphingolipid production may make cancer cells vulnerable to the immune system.
“Everyone thought of increased lipid levels as an energy source for cancer cells,” says Soula. “We found that it’s much more subtle. Lipids are not just fuel, but a protective mechanism for cancer cells that regulates their communication with the immune system.”
Future research will determine whether this is true for many cancers. The team tested a wide range of cancer types, but found that this mechanism works in KRAS-dependent cancers (named because of the mutated oncogene that drives them). Still, the preliminary results could have important clinical implications, given how aggressive many KRAS-dependent cancers, such as pancreatic cancer, are. Based on their findings, the team suggests that drug and dietary interventions that inhibit sphingolipid production could help enhance the efficacy of existing immunotherapies.
“Diet can affect many aspects of cancer biology,” says Birsoy. “We believe that modifying dietary lipids could be an interesting way to target the ability of cancer cells to evade immune cells.”
(Except for the headline, this story has not been edited by NDTV staff and is published from a syndicated feed.)
