Cancer Cells Don’t Just Compete, They Cooperate

It has long been known that cancer cells compete with one another for nutrients and resources, allowing a tumor to become more aggressive over time. However, tumors grow in environments where nutrients are scarce.

Researchers from New York University have uncovered that cancer cells also work together to source nutrients from their environment — a cooperative process that was previously overlooked but may be a promising target for treating cancer. The study was published in Nature.

Cancer cells show cooperation in nutrient-deprived environments

Is it possible that cancer cells work together to scavenge resources in deprived conditions to allow for tumor survival and growth?

Dr. Carlos Carmona-Fontaine, associate professor of biology at New York University, and colleagues aimed to answer this question by tracking cell growth from a range of different tumors.

Using a robotic microscope and image analysis software, they quickly counted millions of cells under hundreds of conditions over time. This allowed Carmona-Fontaine and the team to examine tumor cultures at various densities and with different nutrient availability.

“We started [exploring cancer cell cooperation] from the long-standing and well-known observation that cultured animal cells struggle to grow when seeded at low densities,” Carmona-Fontaine told Technology Networks.

“In a scenario where cells would only compete, being at low density should be ideal: an abundance of resources and no competitors. In contrast, if cells rely on cooperation, they will need neighbors to grow. Thus, at low density, these cells will struggle to find other cells to cooperate with. Since the latter scenario is closer to our observations of tumor cell growth, we knew that these cells must be cooperating somehow,” Carmona-Fontaine said.

“To our surprise, we found that these cells cooperate to withstand starving conditions through a previously unknown form of collective nutrient scavenging.” 

CNDP2 enzyme plays a key role in low amino acid conditions

Cancer cells need large quantities of amino acids to survive, allowing for protein synthesis and energy production, yet tumors grow in environments deprived of these nutrients.

When the cancer cells studied were starved of amino acids such as glutamine, the cells showed a strong need to cooperate to acquire the available nutrients. Carmona-Fontaine and the team also determined that a key source of nutrients for cancer cells comes from oligopeptides – proteins made from small chains of amino acids – found outside the cell.

“We discovered that tumor cells do not pick up these peptides to eat them as they do with other nutrients. Instead, they release a specialized enzyme – CNDP2 – that digests peptides into individual amino acids releasing them into their surroundings,” explained Carmona-Fontaine.

“In addition to being unconventional, this process becomes a form of cell cooperation as every tumor cell that releases this enzyme is providing amino acids for itself as much as for all its neighbors,” he continued.

The researchers identified the enzyme by testing different drugs to see if they inhibited tumor cells from digesting oligopeptides into free amino acids. When bestatin was applied, cancer cells were unable to feed on oligopeptides and were driven to extinction, due to the inhibition of CNDP2.

By applying CRISPR gene editing technology to delete or “knockout” to Cndp2 gene in tumor cells, the team found the growth of the knockout tumors was reduced, with an even more pronounced reduction when combined with restricted amino acid availability.

“From what we can tell, there were no major effects on CNDP2 knockout cells unless they were under low amino acids conditions. Luckily for us, amino acids are scarce within the tumor microenvironment so as we had predicted, CNDP2 knockout cells struggled to form tumors,” said Carmona-Fontaine.

“We propose that CNDP2 is part of this cooperative ‘backup’ mechanism to obtain amino acids. Most cells normally have all the amino acids that they may need, however, if, for some reason amino acid levels are not enough, cells can obtain more of them by ‘mining’ peptides – via CNDP2 secretion – they find in their immediate surroundings,” he added.

Hope for treatments focused on cancer cell cooperation

The researchers hope the results from the study will help inform cancer treatments that target cooperation, not just competition, among cancer cells.

Carmona-Fontaine and the team are excited by this mechanism as it could lead to promising treatment targets for cancer.

“We want to exploit this cooperative mechanism by developing better CNDP2 inhibitors,” Carmona-Fontaine said.

“We are hopeful because this seems to be a backup mechanism where normal cells have enough amino acids delivered by blood circulation. Thus, this function of CNDP2 is redundant in most healthy scenarios,” he explained.

“In contrast, tumors usually have terrible access to the bloodstream and have high demands for amino acids. As a result, the circulating amino acids are not nearly enough for them and they become dependent on the cooperative cleavage of peptides by CNDP2. Because of these reasons – at least in our experiments – we can inhibit this process without significant secondary effects giving us the hope that CNDP2 may be a realistic clinical target.”

Reference: Guzelsoy G, Elorza SD, Ros M, et al. Cooperative nutrient scavenging is an evolutionary advantage in cancer. Nature. 2025. doi: 10.1038/s41586-025-08588-w

About the interviewee

Dr. Carlos Carmona-Fontaine is an associate professor of biology and a member of the Center for Genomics & Systems Biology at New York University. He holds a PhD in cell and developmental biology from University College London (UK) and a BSc in biology from Chile. The main interest of his laboratory is to understand how cells organize to form multicellular structures and how their behaviors may give rise to unexpected collective properties at the population level. These problems of multicellular organization are crucial for physiological processes and during embryonic development, but they are also critical in the formation of malignant tumors. His lab has shown that a significant player in multicellular organization emerges from social and ecological cell interactions mediated by metabolites – nutrients and waste products of cellular activity.

Prior to joining the faculty at NYU, Carmona-Fontaine was an independent research fellow in the computational biology program at the Memorial Sloan Kettering Cancer Center. He received a K99/R00 Pathway to Independence award during his postdoctoral research and was awarded the Beddington Medal for his doctoral studies. As a faculty member, he has received a number of awards including a DP2 New Innovator Award from the NIH, a Pew Biomedical Fellowship and an American Cancer Society research fellowship.