Cooperative nutrient scavenging is an evolutionary advantage in cancer
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Correspondence to: e-mail: [email protected]
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Guzelsoy G, Elorza SD, Ros M, Schachtner LT, Hayashi M, Hobson-Gutierrez S, et al. Cooperative nutrient scavenging is an evolutionary advantage in cancer. Nature. 2025.
The survival of malignant cells within tumours is often seen as depending on ruthless competition for nutrients and other resources. Although competition is certainly critical for tumour evolution and cancer progression, cooperative interactions within tumours are also important, albeit poorly understood. Cooperative populations at all levels of biological organization risk extinction if their population size falls below a critical tipping point. 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.
肿瘤内恶性细胞的生存通常被认为依赖于对营养物质和其他资源的无情竞争。虽然竞争对肿瘤进化和癌症进展肯定至关重要，但肿瘤内的合作相互作用也很重要，尽管我们对其知之甚少。如果它们的种群数量低于临界点，那么所有生物组织层面的合作种群都面临灭绝的风险。在这里，我们研究了肿瘤细胞之间的合作是否可能是一个潜在的治疗靶点。我们发现了一种协同机制，使肿瘤细胞能够在肿瘤微环境中氨基酸缺乏的条件下增殖。这一机制的破坏将培养的肿瘤群体推向临界消退点，并导致体内肿瘤生长的显著减少。在机制上，我们证明了肿瘤细胞通过分泌氨肽酶来集体消化细胞外寡肽。产生的游离氨基酸对分泌氨肽酶的细胞和邻近细胞都有益。我们发现CNDP2是细胞外水解这些肽的关键酶，而这种氨肽酶的缺失可以阻止体内外肿瘤的生长。这些数据表明，协同清除营养物质是肿瘤微环境中生存的关键，并揭示了可靶向的癌症脆弱性。
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