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Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness

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 genot...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10108304/
https://www.ncbi.nlm.nih.gov/pubmed/36408933
http://dx.doi.org/10.1002/ijc.34367
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author 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
author_facet 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
author_sort Czaplinska, Dominika
collection PubMed
description 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 by 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.
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spelling pubmed-101083042023-04-18 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 Int J Cancer Molecular Cancer Biology 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 by 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. John Wiley & Sons, Inc. 2022-12-01 2023-03-15 /pmc/articles/PMC10108304/ /pubmed/36408933 http://dx.doi.org/10.1002/ijc.34367 Text en © 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Molecular Cancer Biology
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
Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness
title Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness
title_full Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness
title_fullStr Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness
title_full_unstemmed Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness
title_short Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness
title_sort crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness
topic Molecular Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10108304/
https://www.ncbi.nlm.nih.gov/pubmed/36408933
http://dx.doi.org/10.1002/ijc.34367
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