Cancer cells are notorious for their ability to adapt. Cut off one fuel source, and they often find another. Now, new research from the laboratory of Alexis Jourdain, PhD, at the University of Lausanne, sheds light on how some tumors can keep growing even when deprived of glutamine—an amino acid many cancers depend on—and identifies a potential vulnerability in tumors carrying mutations in the cancer-associated gene FBXW7.
The study, published in Molecular Cell and led by postdoctoral fellow Miriam Lisci, PhD, reveals that cancer cells can switch to an alternative metabolic pathway driven by pyruvate, a carbon-rich molecule, to sustain proliferation in the absence of glutamine. Crucially, this backup system depends on a mitochondrial enzyme, pyruvate carboxylase, which requires vitamin B7—better known as biotin—to function.
“We were fascinated by the fact that cancer cells are very metabolically flexible,” Lisci said. “They seem to be more flexible than other cell types, and that’s why they’re so good at growing in different environments. If we try to target one pathway, they often find another way around it to survive.”
At the same time, many cancer cells display a pronounced sensitivity to glutamine withdrawal. That paradox—flexibility alongside dependence—prompted the team to ask how tumors cope when glutamine is scarce.
A biotin-dependent backup plan
The researchers found that when glutamine is unavailable, cancer cells can redirect metabolism through pyruvate carboxylase, allowing pyruvate to replenish intermediates in the cell’s energy-producing cycle. However, pyruvate carboxylase is only active when bound to biotin.
“If there is plenty of biotin and the enzyme is present, then the cancer cells will be able to survive even though this amino acid is absent,” Lisci explained. “But if biotin is not there, then this enzyme is not going to be active, and therefore they will be more sensitive to the lack of glutamine.”
In other words, biotin availability determines whether pyruvate can compensate for glutamine loss. Without active pyruvate carboxylase, cells stall when deprived of glutamine.
The pathway itself is not new. Pyruvate carboxylase plays a well-established role in normal physiology, including gluconeogenesis—the process by which the liver generates glucose during fasting.
“When you wake up in the morning and you want to maintain your glucose level in your blood, your body is going to make glucose,” Jourdain said. “So it’s a general pathway. We did not discover the pathway. What we could show is how important it is for cancer cells to grow.”
Importantly, the team demonstrated that this metabolic adaptation becomes particularly critical under glutamine starvation. “The pathway always seems to be active,” Lisci noted. “But we show in our publication that it seems to be more active when glutamine is absent.”
The findings were consistent across multiple cancer models. Although the researchers began with a specific cell line, they extended their analysis to a broad panel of cancer types.
“We looked in 10 or 12 cancer types, and in all of them, this was applicable,” Jourdain said. Lisci added that the results held true across both murine and human cancer cells, suggesting that the mechanism is widely conserved.
Linking FBXW7 mutations to metabolic vulnerability
Beyond identifying this biotin-dependent rescue pathway, the team uncovered a previously unrecognized connection between cancer genetics and metabolic flexibility.
They focused on FBXW7, a tumor suppressor gene frequently mutated in a range of malignancies. Although FBXW7 has been extensively studied, its role in regulating this specific metabolic pathway had not been described.
“What we found quite interesting was among the latest findings that we describe,” Lisci said. “There is a gene called FBXW7 that is very commonly mutated in cancer. When we tried to mimic FBXW7 mutations in our cells, we saw that the cells became very, very sensitive to this glutamine addiction phenotype.”
Mechanistically, mutations in FBXW7 reduced levels of pyruvate carboxylase, impairing the cells’ ability to use pyruvate as an alternative fuel. As a result, these cells could no longer compensate for glutamine loss and became highly dependent on it.
“This is because they actually lack this pathway that goes through biotin and pyruvate carboxylase,” Lisci said. “If we wanted to target cells by starving them of glutamine, then maybe we could potentially target patients who have these mutations, because they might be more sensitive to this kind of nutrient starvation approach.”
Jourdain framed the finding within the broader logic of precision oncology. “That’s the principle of precision medicine,” he said. “Instead of treating the tumor as if it was any tumor, we check what are the mutations in those tumors. If they have the mutation in FBXW7, then we would predict that they would be more sensitive to therapies targeting glutamine metabolism.”
The study also connects these findings to MYC, a well-known oncogene. FBXW7 normally helps degrade MYC; when FBXW7 is mutated, MYC activity increases. The researchers showed that the metabolic rewiring observed in tumors occurs downstream of MYC signaling, further integrating oncogenic signaling with nutrient use.
“MYC is known to be a proliferating factor,” Jourdain said. “But what we show here is we connect it to metabolism, to the metabolism of cancer cells.”
Therapeutic implications and challenges
Targeting tumor metabolism has long been an attractive strategy, but selectively depriving cancer cells of nutrients without harming normal tissues remains challenging.
“It’s hard to deprive cells of a specific nutrient without also the healthy tissue suffering,” Lisci acknowledged.
However, identifying specific enzymes within this pathway may open up alternative strategies. “Now that we have found those enzymes, we could develop inhibitors or use existing inhibitors to target specifically those enzymes,” Jourdain said.
He also emphasized the potential of combination approaches. “We think that eventually we could target two enzymes at the same time,” he said. “If we cut one source of energy and another one, then the cancer cells would not be able to grow.”
Such dual-targeting strategies could exploit tumors’ metabolic dependencies—particularly those already compromised by FBXW7 mutations.
