Adaptation to an acid microenvironment promotes pancreatic cancer organoid growth and drug resistance
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Adaptation to an acid microenvironment promotes pancreatic cancer organoid growth and drug resistance. / Stigliani, Arnaud; Ialchina, Renata; Yao, Jiayi; Czaplinska, Dominika; Dai, Yifan; Andersen, Henriette Berg; Rennie, Sarah; Andersson, Robin; Pedersen, Stine Falsig; Sandelin, Albin.
In: Cell Reports, Vol. 43, No. 7, 114409, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Adaptation to an acid microenvironment promotes pancreatic cancer organoid growth and drug resistance
AU - Stigliani, Arnaud
AU - Ialchina, Renata
AU - Yao, Jiayi
AU - Czaplinska, Dominika
AU - Dai, Yifan
AU - Andersen, Henriette Berg
AU - Rennie, Sarah
AU - Andersson, Robin
AU - Pedersen, Stine Falsig
AU - Sandelin, Albin
N1 - Publisher Copyright: © 2024 The Author(s)
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - CP: Cancer
KW - drug resistance
KW - microenvironment
KW - pH
U2 - 10.1016/j.celrep.2024.114409
DO - 10.1016/j.celrep.2024.114409
M3 - Journal article
C2 - 38944837
AN - SCOPUS:85197507853
VL - 43
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 7
M1 - 114409
ER -
ID: 398477190