New Approach to Cancer Treatment Through Nutrient Deprivation

Scientists have long recognized that cancer cells compete for nutrients, with the most aggressive cells ultimately dominating a tumor. However, new research suggests that cancer cells may also cooperate to secure vital resources—a discovery that could open new avenues for treatment.

"We identified cooperative interactions among cancer cells that allow them to proliferate. Understanding the mechanisms tumor cells exploit can help shape future therapies,"

Carlos Carmona-Fontaine, senior author of the study and associate professor at New York University.

Published in Nature, the study challenges the traditional view that competition is the primary driver of tumor growth. In ecology, cooperation is common in harsh environments—penguins huddle together to conserve heat in winter, while microorganisms like yeast collaborate to locate nutrients during scarcity. Could cancer cells be using a similar strategy?

To explore this, researchers tracked the behavior of different tumor cell types. Using a robotic microscope and custom image-processing software, they analyzed millions of cells under various conditions, ranging from nutrient-rich environments to extreme scarcity.

While it is well known that cells compete for amino acids, the study found that when deprived of nutrients like glutamine, cancer cells exhibited a surprising tendency to cooperate. The research revealed that tumors with higher cell densities benefited from this cooperation, while sparsely populated cultures did not, reinforcing the idea that this is a density-dependent process.

Further experiments with skin, breast, and lung cancer cells pinpointed a key mechanism: instead of consuming protein fragments (oligopeptides) directly, cancer cells secrete an enzyme that breaks them down into free amino acids. This process occurs outside the cells, creating a shared nutrient pool accessible to all.

The enzyme CNDP2 emerged as a crucial player in this cooperative strategy. Researchers tested various drugs and found that bestatin, an existing chemotherapy supplement, blocked CNDP2 function. Without this enzyme, cancer cells lose the ability to break down oligopeptides and ultimately die.

To confirm CNDP2’s role, researchers used CRISPR gene-editing technology to delete the Cndp2 gene in tumor cells. When these modified cells were implanted in mice, tumors lacking CNDP2 grew significantly slower, particularly when combined with a diet low in amino acids. Additionally, pairing bestatin with this restricted diet slowed tumor growth even in cells that still produced CNDP2—highlighting a potential therapeutic approach.

"By removing their ability to secrete CNDP2 and utilize oligopeptides, cancer cells can no longer cooperate, preventing tumor growth," Carmona-Fontaine explained. "While competition remains crucial in cancer progression, our study underscores the importance of cooperative interactions within tumors."

This discovery paves the way for therapies that disrupt cancer cell cooperation. Bestatin, which has been safely used in humans for decades, could be made more effective when combined with targeted treatments.

"A deeper understanding of this mechanism could help us develop more precise and potent drugs," Carmona-Fontaine concluded.

This research marks a significant step toward exploiting cancer’s own cooperative strategies against it, offering fresh possibilities for therapeutic intervention.