The metabolic adaptations that cancer cells make to survive also present new drug opportunities, a new study shows.
The study, published in Molecular Cell, suggests that targeting a vitamin B7-dependent pathway could be one way to limit the growth of glutamine-independent cancers.
Adaptations to survive
Dysfunctional vasculature in the microenvironment of solid tumors limits the availability of nutrients and oxygen, forcing cancer cells to undergo several adaptations to support growth.
Cancer cells become increasingly reliant on glycolysis—an metabolic pathway—even when oxygen is available. They also reprogram lipid metabolism, upregulate pathways that protect against oxidative stress, and drive plasticity in cell migration programs that contribute to metastasis.
“Another major adaptation is an increased dependence on glutamine metabolism, as glutamine provides both carbon and nitrogen to fuel the tricarboxylic acid (TCA) cycle and support the synthesis of essential biomolecules,” Prof. Alexis A. Jourdain, an assistant professor at the University of Lausanne who led the team behind the new research, told Technology Networks. “This reliance on glutamine as a key metabolic fuel is the aspect we investigated in our study.”
Glutamine dependency
The “glutamine addiction” phenomenon, where cells become dependent on extracellular glutamine, is thought to occur when cells proliferate so rapidly that they exceed the capacity of intracellular biosynthesis.
Glutamine
Glutamine is the most abundant amino acid in human plasma. It is viewed as a non-essential amino acid—it is produced naturally by the body and therefore does not need to be obtained from the diet. As well as forming a building block for proteins, glutamine contributes to ATP generation by fuelling the TCA cycle, and serves as both a carbon and amine donor in additional metabolic reactions, including amino acid synthesis and reactions necessary for nitrogen metabolism.
“Glutamine is a critical nutrient for cancer cells because it supports many of the processes they need to grow and divide rapidly,” explained Dr. Miriam Lisci, first author of the new research.
As a building block for protein synthesis, glutamine supports the constant production of proteins needed for cancer cells to build new cells.
“Glutamine provides carbon that feeds into the TCA cycle, which is a central metabolic pathway inside mitochondria that helps cells generate energy and produce important metabolic intermediates,” Lisci said. “This energy and these molecules are essential to sustain rapid growth.”
It also supplies nitrogen for nucleotide synthesis, enabling DNA replication and cell division.
“Because glutamine contributes to protein production, DNA synthesis, and energy metabolism all at once, it becomes especially important for highly proliferative cells like cancer cells,” Lisci said. “However, some cancers adapt to the absence of glutamine by rewiring their metabolism, and they use alternative nutrients to fuel the same essential requirements.”
Overcoming glutamine dependency
Lisci, Jordain, and their colleagues set out to identify the nutrients and metabolic pathways that help cancer cells to overcome glutamine dependency.
“By discovering these backup strategies, we aim to find ways to cut off the cancer cells’ escape routes and make them more vulnerable to treatment,” Lisci explained.
Using a large-scale nutrient screen that systematically tested hundreds of nutrients, the team found that carboxylic acids, such as pyruvate, enables cancer growth in the absence of glutamine.
Pyruvate
Pyruvate is a three-carbon intermediate in glucose metabolism that feeds into the citric acid cycle. It plays a key role in gluconeogenesis and fatty acid synthesis when metabolised to oxaloacetate by pyruvate carboxylase.
The researchers then looked at the genes that are essential for cell survival without glutamine, which led them to the tumor suppressor FBXW7 and pyruvate carboxylase.
Pyruvate carboxylase, an enzyme dependent on vitamin B7 (also known as biotin), is one of the enzymes that allows cells to use pyruvate to feed carbon into the TCA cycle, producing important molecules, such as amino acids.
“Without biotin, the enzyme remains inactive, even if pyruvate is abundant,” explained Lisci. “In that sense, biotin acts like a ‘metabolic licence’ as it gives the enzyme permission to operate.”
“We discovered that some cancer cells are not addicted to glutamine because they use this biotin-dependent pathway as a backup system. When glutamine is unavailable, they reroute their metabolism and rely on pyruvate carboxylase to keep the TCA cycle running,” she said. “This metabolic flexibility makes cancer cells particularly resilient, and biotin is essential for this switch.”
The team used genetic tools to validate the mechanism in different cell models, illustrating that the biotin-dependent back-up system exists in multiple cancer types with different origins.
“If we can block biotin availability in tumors, or inhibit pyruvate carboxylase, we may be able to shut down this backup pathway,” Lisci said. “That could make glutamine-independent cancers more vulnerable to drugs targeting glutamine metabolism and limit their growth.”
An unexpected role for FBXW7
FBXW7 is involved in the ubiquitin-proteasome system, controlling the proteasome-mediated degradation of oncoproteins and the stability of key cell growth proteins.
“Our work reveals that it also plays an unexpected role in regulating cancer cell metabolism by affecting glutamine addiction and the biotin-dependent backup strategy,” Lisci said.
Cancer-associated mutations to FBXW7 were associated with a decrease in pyruvate carboxylase expression, leading to cancer cells becoming reliant on glutamine as they couldn’t use pyruvate as an alternative fuel source.
This metabolic vulnerability could be a target for new therapeutics: “If FBXW7-mutant tumors are less able to compensate when glutamine is limited, then targeting glutamine metabolism may selectively weaken these cancers and reduce tumor growth,” explained Lisci.
Targeting metabolic vulnerabilities
Targeting two or more pathways at the same time removes the cancer cell’s ability to compensate, increasing the likelihood of the treatments being successful.
“I believe the most promising strategies to exploit cancer’s metabolic vulnerabilities involve combination therapies that target a metabolic dependency together with the cell’s ‘plan B’,” said Jourdain.
“Additional promising vulnerabilities are also being explored in combination strategies, such as applying stresses on pathways of the cellular redox machinery, or reshaping the metabolic landscape of tumors in combination with immunotherapy,” he noted.
As well as opening new avenues for targeting the metabolic vulnerabilities of tumor cells, the new work also highlights why glutamine-targeting cancer therapies sometimes fail, an insight that could shape cancer treatment.
Reference: Lisci M, Vericel F, Liu Y, et al. Functional nutrient-genetic profiling reveals biotin and FBXW7 are essential to bypass glutamine addiction. Mol Cell. 2026;86(5):901-916.e10. doi: 10.1016/j.molcel.2026.02.002
About the interviewees:
Prof. Alexis Jourdain is an assistant professor at the University of Lausanne. He obtained his PhD in 2013 from the University of Geneva for his work on mitochondrial gene expression and mitochondrial RNA granules. During his postdoctoral training as a fellow of the European Molecular Biology Organization (EMBO) and the Swiss National Science Foundation (SNSF), he used systems biology approaches to discover nuclear genes involved in energy metabolism, including genes encoding mitochondrial subunits and pre-mRNA splicing subunits. In spring 2021, he joined the Department of Immunobiology (formerly Biochemistry) at the University of Lausanne as a tenure-track assistant professor, and since 2026, he has been an EMBO Young Investigator. His group studies mitochondria and energy metabolism and their regulation in immunity, cancer, and metabolic disorders.
Dr. Miriam Lisci is currently a postdoctoral researcher at the University of Lausanne (Department of Immunobiology) working in the team of Prof. Alexis Jourdain. She joined the lab as an EMBO postdoctoral fellow, investigating the metabolic networks mediating nutrient addiction in cancer cells. Dr. Lisci obtained her PhD from the University of Cambridge, where she investigated the role of mitochondria in regulating the function of cytotoxic T cells.
