Certain lipids discovered in the 1800s presented chemists with structural and functional puzzles that proved unsolvable. And so, the chemists called these lipids sphingolipids, likening them to the mythological sphinx, a monster that challenged travelers to solve her riddles. The name is more apt than the chemists knew. Besides being mysterious, sphingolipids resemble the sphinx in another respect. They can be dangerous, even deadly, when their puzzles remain unsolved. Fortunately, thanks to a new study by Rockefeller University scientists, at least one outstanding sphingolipid mystery has been solved.
The study’s findings appeared in Nature, in a paper titled, “Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer.” It describes how glycosphingolipids, from their lair within the cancer cell’s membrane, effectively smother the signals that would alert the immune system, if only they could be unsuppressed.
“[Using] functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion,” the article’s authors reported. “Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8+ T cells partly via interferon-γ (IFNγ) signaling.”
These findings confirm longstanding suspicions that not only is this lipid a key player in cancer biology (and therefore a key drug target), but also demonstrate that existing FDA-approved medications designed to stunt lipid production can galvanize the immune system against cancer. More generally, the findings indicate that in cancer, lipids do more than serve a well-known role as a fuel source for burgeoning tumors.
“Cancer cells are altering how this lipid is metabolized, which in turn distorts the ‘eat me’ signals that malignant cells usually produce,” said the Nature paper’s first author Mariluz Soula, PhD, a former graduate student in the laboratory of Kivanç Birsoy, PhD, and now a scientist at Lime Therapeutics. “This paints a very different picture of the role lipids play in cancer growth.”
Scientists have long known that cancer cells alter lipid metabolism, but it was generally assumed that cancer cells were gobbling up these lipids for energy—consuming the fatty molecules to help the tumor grow and spread far beyond that of healthy cells.
“We knew from the literature that elevated lipid levels correlate with severity of cancer growth and metastasis, but it was unclear how,” Soula said. The Birsoy lab, in conjunction with the laboratory of Gabriel D. Victoria, PhD, set out to answer this question by screening the genes involved in this process. They then implanted a series of cancer cells, each missing a different such gene, into mice with and without immune systems—thereby revealing which lipids a cancer cannot live without.
“We know that sphingolipids aren’t really used for energy,” Soula said. “They’re mainly in the cell membrane to create scaffolding for signaling proteins.”
The scientists also explored the therapeutic implications of their work.
“Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signaling,” they wrote. “Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response.”
To test how sphingolipids were driving cancer growth, the team turned to an FDA-approved drug used to treat Gaucher disease—a genetic disorder characterized by an impaired ability to break down lipids. The drug essentially blocks glycosphingolipid synthesis, and the team found that this impaired tumor growth in pancreatic, lung, and colorectal cancer models.
They also found that depleting glycosphingolipids prevented the formation of the “lipid nanodomains” that bunch signalizing molecules together on the membrane, impacting the cell’s surface receptors on the cell surface in a way that made them more sensitive to an immune response. These findings suggest that cancer cells hoard glycosphingolipids in order to obscure inflammatory signals, and that disrupting glycosphingolipid production can leave cancer cells vulnerable to the immune system.
“Everyone thought of elevated lipid levels as an energy source for cancer cells to consume,” Soula said. “We discovered that it’s far more nuanced. Lipids are not just fuel, but a protection mechanism for cancer cells that modulates how they communicate with the immune system.”
Future work will determine whether this holds true for multiple cancers. The team tested a variety of types but found this mechanism at work in KRAS-dependent cancers (so named for the mutated oncogene that drives them). Still, the initial results could have significant clinical impact, given how aggressive many KRAS-dependent cancers, such as pancreatic cancer, tend to be. Based on their findings, the team suggests that drug and dietary interventions that stunt sphingolipid production may help increase the efficacy of existing immunotherapies.
“Diets may impact many aspects of cancer biology,” Birsoy said. “We believe modulating dietary lipids may be an interesting avenue to target cancer cells’ ability to evade immune cells.”
