West LA Times

UCLA researchers have discovered that squamous cell skin cancers exhibit metabolic flexibility, allowing them to switch nutrient sources and resist treatments targeting a single metabolic pathway. The study underscores the potential of combination therapies that simultaneously target multiple metabolic pathways to more effectively combat skin cancer and other cancers with similar metabolic profiles. The findings could ultimately lead to a topical treatment that directly targets skin tumors, offering a potentially safer and more effective alternative to systemic therapies.

Scientists at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have identified key metabolic mechanisms that squamous cell skin cancers use to resist treatment, offering new insights into how to potentially stop cancer growth.

Their findings, published in Science Advances, highlight the need for combination therapies that target multiple metabolic pathways simultaneously. This approach could lead to more effective therapies not only for squamous cell skin cancer, which forms in cells on the surface of the skin but also for myriad other cancers that share similar metabolic hallmarks.

The research was led by senior author William Lowry, a professor of molecular, cell and developmental biology at UCLA.

In 2019, Lowry and his colleagues overturned a fundamental doctrine of cancer metabolism theory known as the Warburg effect, which stated that cancer cells primarily rely on glucose for energy. Instead, they found that squamous cell skin cancer cells are metabolically flexible: When glucose is unavailable, they can switch to derive energy from the amino acid glutamine.

“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 work, Carlos Galván, a graduate student in Lowry’s lab and the new study’s first author has been investigating the extent of this metabolic flexibility and whether it could be curtailed. Working with mouse models, he genetically blocked the pathway glutamine uses to fuel cells in hair follicle stem cells—a known cell type of origin for squamous cell skin cancer—and observed its effect on the formation and growth of tumors. As with previous experiments, the tumors simply switched to another nutrient source.

“It’s kind of like whack-a-mole,” said Galván, who is also part of the UCLA Broad Stem Cell Research Center Training Program. “When you block one metabolic pathway, the cancer cells are just flexible enough to find another nutrient to fuel their growth.”

Next, researchers tried what they call a “double hammer” approach: genetically blocking pathways for both glucose and glutamine metabolism by deleting transmitters allowing uptake of respective enzymes. This dual-target strategy was enough to prevent cancer from growing in mouse models.

Galván also sought to identify mechanisms enabling cancer cells to rewire their metabolic programs when one nutrient pathway was blocked. Interestingly, he found that metabolic flexibility was not driven by a transcriptional response but by rapid redistribution of transporter proteins to cell membranes allowing uptake of alternative nutrients.

The research team is working on replicating their genetic findings using pharmacological inhibitors targeting specific enzymes involved in these processes. To bring this therapeutic strategy to patients, they are focused on identifying and testing combinations of drugs achieving effects observed with genetic manipulation.

Adding complexity is their interest in developing topical treatments applied directly to skin tumors—offering advantages such as minimizing side effects seen with oral treatments.

“One advantage of treating skin cancer is accessibility,” Galván said. “Applying treatment topically could be more effective and safer than systemic treatments but challenges remain such as ensuring drug penetration through skin barriers.”

Because various other cancers also use glucose and glutamine for growth fuel implications extend beyond squamous cell skin cancer; researchers are applying strategies tested here onto other cancers like melanoma while exploring protein/post-transcriptional regulation enabling flexibility.

“If we can figure out how cancer cells sense/respond under stress we might target underlying mechanisms defeating them in questing flexibility,” said Lowry who co-directs education/training/mentoring at UCLA Health Jonsson Comprehensive Cancer Center adding it may offer alternatives over just blocking transporters pharmacologically.”

Experimental drugs mentioned were used preclinically not FDA-approved yet for human usage; study support came via National Institute Arthritis Musculoskeletal Skin Diseases/National Cancer Institute/Galván received support through various training programs/scholarships listed below:

Other authors include Aimee Flores Victoria Cerrillos Itzetl Avila Conor Murphy Heather Christofk Wilson Zheng.