灌注不良的肿瘤区域的恶劣环境可能会选择驱动癌症侵袭性的特征。在这里，我们研究了肿瘤酸中毒是否与驱动突变相互作用以加剧癌症特征。我们将来自正常胰管 (mN10) 和早期胰腺癌 (mP4、KRAS-G12D 突变、± p53 敲除) 的小鼠类器官从细胞外 pH 7.4 调整到 6.7，代表酸性生态位。酸性适应可增加活力，这种模式在野生型 (WT) p53 类器官中最为明显，并且在 pH 值恢复到 7.4 时会加剧。这导致用吉西他滨和/或厄洛替尼治疗的酸适应类器官的存活率增加，并且在WT p53类器官中，酸诱导的药物作用减弱。新的遗传变异在适应过程中占据主导地位，但它们不太可能成为其主要驱动力。酸和药物适应引起的转录变化总体上不同，但酸适应增加了吉西他滨耐药基因的表达。因此，对酸中毒的适应会增加化疗后癌细胞的活力。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Harsh environments in poorly perfused tumor regions may select for traits driving cancer aggressiveness. Here, we investigated whether tumor acidosis interacts with driver mutations to exacerbate cancer hallmarks. We adapted mouse organoids from normal pancreatic duct (mN10) and early pancreatic cancer (mP4, KRAS-G12D mutation, ± p53 knockout) from extracellular pH 7.4 to 6.7, representing acidic niches. Viability was increased by acid adaptation, a pattern most apparent in wild-type (WT) p53 organoids, and exacerbated upon return to pH 7.4. This led to increased survival of acid-adapted organoids treated with gemcitabine and/or erlotinib, and, in WT p53 organoids, acid-induced attenuation of drug effects. New genetic variants became dominant during adaptation, yet they were unlikely to be its main drivers. Transcriptional changes induced by acid and drug adaptation differed overall, but acid adaptation increased the expression of gemcitabine resistance genes. Thus, adaptation to acidosis increases cancer cell viability after chemotherapy.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.