Healthcare (Commonwealth Union) – Researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have uncovered crucial metabolic processes that enable squamous cell skin cancers to evade treatment, shedding light on new strategies to halt cancer progression.
The study, that appeared in Science Advances, emphasizes the importance of developing combination therapies that target multiple metabolic pathways at once. This strategy has the potential to improve treatment outcomes not only for squamous cell skin cancer, which arises from surface skin cells, but also for various other cancers with similar metabolic characteristics.
The research was headed by William Lowry, a professor of molecular, cell, and developmental biology at UCLA.
Lowry and his team have previously challenged a longstanding concept in cancer metabolism, known as the Warburg effect, which proposed that cancer cells mainly rely on glucose for energy. Their findings revealed that squamous cell skin cancer cells are metabolically adaptable: when deprived of glucose, they can switch to using the amino acid glutamine as an alternative energy source.
Professor Thomas Seyfried has also reveled similar findings in research where he has proposed effective methods to target cancer cells by targeting both glucose and glutamine. Professor Seyfried has indicated that much of the formation of cancer cells originate in the mitochondrial dysfunction within the cell.
“Our data suggest that the reason previous clinical efforts to target cancer metabolism have failed is that they focused on just one pathway at a time,” said Lowry, associate director of education and technology transfer at the UCLA Broad Stem Cell Research Center. “In a living organism, there are multiple nutrients available that tumors can use to fuel their growth, making single-pathway interventions insufficient.”
Building on this research, Carlos Galván, a graduate student in Lowry’s lab and lead author of the new study, has been exploring the extent of this metabolic flexibility and whether it can be limited. Using mouse models, he genetically blocked the pathway that allows glutamine to fuel hair follicle stem cells—a known origin point for squamous cell skin cancer—and studied its impact on tumor growth. However, just like in earlier experiments, the tumors adapted by switching to another nutrient source.
Galván, who is also part of the UCLA Broad Stem Cell Research Center Training Program indicated that it is like playing whack-a-mole. He further pointed out that when you block one metabolic pathway, the cancer cells are adaptable enough to find another nutrient to sustain their growth.
The researchers then employed a “double hammer” approach: blocking both glucose and glutamine metabolic pathways by deleting the transporters responsible for enzyme uptake. This dual-target method was successful in preventing tumor growth in the mouse models.
Galván also sought to uncover how cancer cells manage to rewire their metabolism to keep growing when one nutrient supply is cut off. Surprisingly, he discovered that this flexibility wasn’t due to a transcriptional response, as previously thought, but instead resulted from a rapid redistribution of transporter proteins to the cell membrane, enabling the cells to absorb alternative nutrients.
The research team is now focusing on replicating their genetic discoveries with the application of pharmacological inhibitors to block the specific enzymes driving these metabolic pathways. Their goal is to translate this therapeutic strategy to patients by identifying and testing the optimal combination of drugs that can produce the same results as the genetic interventions.
Further complicating their efforts, the team is also aiming to develop a topical treatment that could be applied directly to the skin. This method has a distinct advantage: it allows for precise targeting of the tumor site, which could reduce the side effects typically associated with oral medications.
