Cancer cells collaborate to survive challenging conditions

Cancer cells have recently been shown to collaborate to obtain vital nutrients from their environment, a phenomenon that was overlooked in the past. 

This unexpected discovery may offer new avenues to combat tumors by targeting how they share the resources essential for their survival and growth.

The study was carried out by researchers at New York University led by Carlos Carmona-Fontaine, an associate professor of biology.

“We identified cooperative interactions among cancer cells that allow them to proliferate,” Carmona-Fontaine said. “Thinking about the mechanisms that tumor cells exploit can inform future therapies.”

Cancer cells compete and collaborate

For years, it has been well-established that cancer cells primarily compete for resources to gain an edge over neighboring cells. Eventually, this internal rivalry leads to increasingly aggressive tumors steered by the hardiest cells. 

At the same time, ecologists point out that many organisms cooperate under stressful conditions – penguins crowd together for warmth in extreme cold, for instance, and yeast works collectively to search for nutrients when food is scarce. 

Because cancer cells frequently inhabit low-nutrient environments, the researchers questioned whether these cells might also engage in cooperative behaviors for survival.

Signs that cancer cells collaborate 

To explore the possibility of cooperation, the team used a robotic microscope and specialized image analysis software to monitor various types of cancer cells as they grew. They varied both the density of the cell cultures and the levels of nutrients available, observing how these conditions affected the cells over time. 

In doing so, they uncovered a strong tendency for tumor cells – when starved of key amino acids like glutamine – to band together in order to secure nutrients.

“Surprisingly, we observed that limiting amino acids benefited larger cell populations, but not sparse ones, suggesting that this is a cooperative process that depends on population density,”  Carmona-Fontaine explained. “It became really clear that there was true cooperation among tumor cells.”

Sharing nutrients through external enzymes

Further examination of skin, breast, and lung cancer cells revealed that the tumors tapped into a shared source of amino acids from oligopeptides – protein fragments made up of short chains of amino acids – found outside the cell.

“Where this process becomes cooperative is that instead of grabbing these peptides and ingesting them internally, we found that tumor cells secrete a specialized enzyme that digests these peptides into free amino acids,” Carmona-Fontaine said. 

“Because this process happens outside the cells, the result is a shared pool of amino acids that becomes a common good.”

By converting protein fragments into readily available nutrients outside the cell, cancer cells effectively create a collective resource, enhancing their growth potential.

Targeting the key enzyme

The researchers pinpointed CNDP2 as the enzyme responsible for breaking down these oligopeptides. To confirm the importance of CNDP2, they tested different drugs for their ability to block cancer cells from transforming oligopeptides into amino acids. 

The drug bestatin, a known CNDP2 inhibitor, prevented cancer cells from extracting nutrients and ultimately drove them to extinction. 

Next, the team employed CRISPR gene-editing technology to eliminate the CNDP2 gene entirely, thus stopping cells from producing the enzyme and disrupting their cooperative nutrient-sharing.

A direct hit on tumor growth

When these genetically modified cells were introduced into mice, they formed tumors at a greatly reduced rate compared to unaltered cells. Restricting amino acids in the diet amplified this effect, further limiting tumor development in cells lacking CNDP2. 

Moreover, cells with normal CNDP2 could also be suppressed by combining bestatin with a low-amino-acid diet.

“Because we’ve removed their ability to secrete the enzyme and to use the oligopeptides in their environment, cells without CNDP2 can no longer cooperate, which prevents tumor growth,” Carmona-Fontaine said. 

“Competition is still critical for tumor evolution and cancer progression, but our study suggests that cooperative interactions within tumors are also important.”

Hindering tumor collaboration 

The researchers believe that these insights could inspire treatments designed to disrupt cooperation among cancer cells. According to Carmona-Fontaine, their findings represent “a conceptual contribution that will have an impact in the clinic.” 

Bestatin, which has been used safely in humans for decades – particularly in Japan – as a supplement to chemotherapy, has shown limited effectiveness when given alone.

“We hope that a clearer understanding of this mechanism can help us make drugs more targeted and more effective,” Carmona-Fontaine said. 

By aiming therapies at this shared nutrient pool, clinicians could hamper cancer cell growth before the tumors evolve into more resistant forms. This approach of hindering tumor collaboration may offer a novel angle in the ongoing battle against cancer.

The research is published in the journal Nature. 

Image Credit: Carmofon lab/NYU

—–

Like what you read? Subscribe to our newsletter for engaging articles, exclusive content, and the latest updates.

Check us out on EarthSnap, a free app brought to you by Eric Ralls and Earth.com.

—–