为了了解癌细胞如何适应这些挑战，研究人员进行了连续的CRISPR筛选，以鉴定在细胞培养中特定代谢应激条件下影响细胞适应性的基因，然后探索它们在胰腺肿瘤中的相关性。对数百个适合基因的比较分析表明，体内的癌症代谢是由对肿瘤酸中毒的生物能量适应形成的。从机制上讲，酸中毒抑制胞外信号调节激酶（ERK）的胞质活性，从而防止癌基因诱导的线粒体断裂，促进线粒体主题化。由此产生的线粒体呼吸增强支持癌细胞适应各种代谢压力。因此，酸中毒是一种环境因素，它改变了能量代谢，促进了癌症患者的压力恢复能力。
据悉，恶性肿瘤的特点是多种代谢应激，包括营养缺乏、缺氧和代谢副产物的积累。
附：英文原文
Title: Acidosis orchestrates adaptations of energy metabolism in tumors
Author: Sven Groessl, Robert Kalis, Marteinn T. Snaebjornsson, Leon Wambach, Jakob Haider, Florian Andersch, Almut Schulze, Wilhelm Palm, Johannes Zuber
Issue&Volume: 2025-10-09
Abstract: Malignant tumors are characterized by diverse metabolic stresses, including nutrient shortages, hypoxia, and buildup of metabolic by-products. To understand how cancer cells adapt to such challenges, we conducted sequential CRISPR screens to identify genes that affect cellular fitness under specific metabolic stress conditions in cell culture and to then probe their relevance in pancreatic tumors. Comparative analyses of hundreds of fitness genes revealed that cancer metabolism in vivo was shaped by bioenergetic adaptations to tumor acidosis. Mechanistically, acidosis suppressed cytoplasmic activity of extracellular signal–regulated kinase (ERK), thereby preventing oncogene-induced mitochondrial fragmentation and promoting fused mitochondria. The resulting boost in mitochondrial respiration supported cancer cell adaptations to various metabolic stresses. Thus, acidosis is an environmental factor that alters energy metabolism to promote stress resilience in cancer.
DOI: adp7603
Source: https://www.science.org/doi/10.1126/science.adp7603