Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness
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Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness. / Czaplinska, Dominika; Ialchina, Renata; Andersen, Henriette Berg; Yao, Jiayi; Stigliani, Arnaud; Dannesboe, Johs; Flinck, Mette; Chen, Xiaoming; Mitrega, Jakub; Gnosa, Sebastian Peter; Dmytriyeva, Oksana; Alves, Frauke; Napp, Joanna; Sandelin, Albin; Pedersen, Stine Falsig.
In: International Journal of Cancer, Vol. 152, No. 6, 2023, p. 1210-1225.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness
AU - Czaplinska, Dominika
AU - Ialchina, Renata
AU - Andersen, Henriette Berg
AU - Yao, Jiayi
AU - Stigliani, Arnaud
AU - Dannesboe, Johs
AU - Flinck, Mette
AU - Chen, Xiaoming
AU - Mitrega, Jakub
AU - Gnosa, Sebastian Peter
AU - Dmytriyeva, Oksana
AU - Alves, Frauke
AU - Napp, Joanna
AU - Sandelin, Albin
AU - Pedersen, Stine Falsig
N1 - Publisher Copyright: © 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
PY - 2023
Y1 - 2023
N2 - Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with minimal treatment options and a global rise in prevalence. PDAC is characterized by frequent driver mutations including KRAS and TP53 (p53), and a dense, acidic tumor microenvironment (TME). The relation between genotype and TME in PDAC development is unknown. Strikingly, when wild type (WT) Panc02 PDAC cells were adapted to growth in an acidic TME and returned to normal pH to mimic invasive cells escaping acidic regions, they displayed a strong increase of aggressive traits such as increased growth in 3-dimensional (3D) culture, adhesion-independent colony formation and invasive outgrowth. This pattern of acidosis-induced aggressiveness was observed in 3D spheroid culture as well as upon organotypic growth in matrigel, collagen-I and combination thereof, mimicking early and later stages of PDAC development. Acid-adaptation-induced gain of cancerous traits was further increased p53 knockout (KO), but only in specific extracellular matrix (ECM) compositions. Akt- and Transforming growth factor-β (TGFβ) signaling, as well as expression of the Na+/H+ exchanger NHE1, were increased by acid adaptation. Whereas Akt inhibition decreased spheroid growth regardless of treatment and genotype, stimulation with TGFβI increased growth of WT control spheroids, and inhibition of TGFβ signaling tended to limit growth under acidic conditions only. Our results indicate that a complex crosstalk between tumor acidosis, ECM composition and genotype contributes to PDAC development. The findings may guide future strategies for acidosis-targeted therapies.
AB - Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with minimal treatment options and a global rise in prevalence. PDAC is characterized by frequent driver mutations including KRAS and TP53 (p53), and a dense, acidic tumor microenvironment (TME). The relation between genotype and TME in PDAC development is unknown. Strikingly, when wild type (WT) Panc02 PDAC cells were adapted to growth in an acidic TME and returned to normal pH to mimic invasive cells escaping acidic regions, they displayed a strong increase of aggressive traits such as increased growth in 3-dimensional (3D) culture, adhesion-independent colony formation and invasive outgrowth. This pattern of acidosis-induced aggressiveness was observed in 3D spheroid culture as well as upon organotypic growth in matrigel, collagen-I and combination thereof, mimicking early and later stages of PDAC development. Acid-adaptation-induced gain of cancerous traits was further increased p53 knockout (KO), but only in specific extracellular matrix (ECM) compositions. Akt- and Transforming growth factor-β (TGFβ) signaling, as well as expression of the Na+/H+ exchanger NHE1, were increased by acid adaptation. Whereas Akt inhibition decreased spheroid growth regardless of treatment and genotype, stimulation with TGFβI increased growth of WT control spheroids, and inhibition of TGFβ signaling tended to limit growth under acidic conditions only. Our results indicate that a complex crosstalk between tumor acidosis, ECM composition and genotype contributes to PDAC development. The findings may guide future strategies for acidosis-targeted therapies.
KW - extracellular matrix
KW - invasion
KW - organotypic culture
KW - spheroids
KW - tumor microenvironment
U2 - 10.1002/ijc.34367
DO - 10.1002/ijc.34367
M3 - Journal article
C2 - 36408933
AN - SCOPUS:85143443757
VL - 152
SP - 1210
EP - 1225
JO - Acta - Unio Internationalis Contra Cancrum
JF - Acta - Unio Internationalis Contra Cancrum
SN - 0898-6924
IS - 6
ER -
ID: 328549350