Cooperative nutrient scavenging is an evolutionary advantage in cancer

Gizem Guzelsoy, Setiembre D. Elorza, Manon Ros, Logan T. Schachtner, Makiko Hayashi, Spencer Hobson-Gutierrez, Parker Rundstrom, Julia S. Brunner, Ray Pillai, William E. Walkowicz, Lydia W. S. Finley, Maxime Deforet, Thales Papagiannakopoulos and Carlos Carmona-Fontaine ()
Additional contact information
Gizem Guzelsoy: New York University
Setiembre D. Elorza: New York University
Manon Ros: New York University
Logan T. Schachtner: New York University
Makiko Hayashi: New York University Langone Health
Spencer Hobson-Gutierrez: New York University
Parker Rundstrom: New York University
Julia S. Brunner: Memorial Sloan Kettering Cancer Center
Ray Pillai: New York University Langone Health
William E. Walkowicz: Chemitope Glycopeptide
Lydia W. S. Finley: Memorial Sloan Kettering Cancer Center
Maxime Deforet: Laboratoire Jean Perrin (LJP)
Thales Papagiannakopoulos: New York University Langone Health
Carlos Carmona-Fontaine: New York University

Nature, 2025, vol. 640, issue 8058, 534-542

Abstract: Abstract The survival of malignant cells within tumours is often seen as depending on ruthless competition for nutrients and other resources1,2. Although competition is certainly critical for tumour evolution and cancer progression, cooperative interactions within tumours are also important, albeit poorly understood3,4. Cooperative populations at all levels of biological organization risk extinction if their population size falls below a critical tipping point5,6. Here we examined whether cooperation among tumour cells may be a potential therapeutic target. We identified a cooperative mechanism that enables tumour cells to proliferate under the amino acid-deprived conditions found in the tumour microenvironment. Disruption of this mechanism drove cultured tumour populations to the critical extinction point and resulted in a marked reduction in tumour growth in vivo. Mechanistically, we show that tumour cells collectively digest extracellular oligopeptides through the secretion of aminopeptidases. The resulting free amino acids benefit both aminopeptidase-secreting cells and neighbouring cells. We identified CNDP2 as the key enzyme that hydrolyses these peptides extracellularly, and loss of this aminopeptidase prevents tumour growth in vitro and in vivo. These data show that cooperative scavenging of nutrients is key to survival in the tumour microenvironment and reveal a targetable cancer vulnerability.

Date: 2025
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DOI: 10.1038/s41586-025-08588-w

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