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Oxidative stress induces monocyte‐to‐myofibroblast transdifferentiation through p38 in pancreatic ductal adenocarcinoma

BACKGROUND: Cancer‐associated fibroblasts (CAFs) are among the most prominent cells during the desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC). However, CAFs are heterogeneous and the precise origins are not fully elucidated. This study aimed to explore whether monocytes can transdi...

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Autores principales: Huang, Xin, He, Chaobin, Hua, Xin, Kan, Anna, Mao, Yize, Sun, Shuxin, Duan, Fangting, Wang, Jun, Huang, Peng, Li, Shengping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403727/
https://www.ncbi.nlm.nih.gov/pubmed/32508052
http://dx.doi.org/10.1002/ctm2.41
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author Huang, Xin
He, Chaobin
Hua, Xin
Kan, Anna
Mao, Yize
Sun, Shuxin
Duan, Fangting
Wang, Jun
Huang, Peng
Li, Shengping
author_facet Huang, Xin
He, Chaobin
Hua, Xin
Kan, Anna
Mao, Yize
Sun, Shuxin
Duan, Fangting
Wang, Jun
Huang, Peng
Li, Shengping
author_sort Huang, Xin
collection PubMed
description BACKGROUND: Cancer‐associated fibroblasts (CAFs) are among the most prominent cells during the desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC). However, CAFs are heterogeneous and the precise origins are not fully elucidated. This study aimed to explore whether monocytes can transdifferentiate into fibroblasts in PDAC and evaluate the clinical significance of this event. METHODS: CD14(+) monocytes were freshly isolated from human peripheral blood. Immunofluorescence, reverse transcription‐quantitative PCR, western blot, flow cytometry and enzyme‐linked immunosorbent assay were used to detect the expression of αSMA, fibronectin, and other relevant molecules. In addition, latex beads with a mean particle size of 2.0 µm were used to assess the phagocytic capacity. Moreover, RNA sequencing (RNA‐seq) was performed to identify the differences induced by H(2)O(2) and the underlying mechanisms. RESULTS: Immunofluorescence identified αSMA and fibroblast‐specific protein 1 expression by tumor‐associated macrophages in PDAC. The in vitro experiment revealed that oxidative stress (H(2)O(2) or radiation) induced monocyte‐to‐myofibroblast transdifferentiation (MMT), as identified by upregulated αSMA expression at both the RNA and protein levels. In addition, compared with freshly isolated monocytes, human monocyte‐derived macrophages increased fibronectin expression. RNA‐seq analysis identified p53 activation and other signatures accompanying this transdifferentiation; however, the p53 stabilizer nutlin‐3 induced αSMA expression through reactive oxygen species generation but not through the p53 transcription/mitochondria‐dependent pathway, whereas the p38 inhibitor SB203580 could partially inhibit αSMA expression. Finally, MMT produced a unique subset of CAFs with reduced phagocytic capacity that could promote the proliferation of pancreatic cancer cells. CONCLUSIONS: Oxidative stress in the tumor microenvironment could induce MMT in PDAC, thus inducing reactive stroma, modulating immunosuppression, and promoting tumor progression. Reducing oxidative stress may be a promising future therapeutic regimen.
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spelling pubmed-74037272020-08-06 Oxidative stress induces monocyte‐to‐myofibroblast transdifferentiation through p38 in pancreatic ductal adenocarcinoma Huang, Xin He, Chaobin Hua, Xin Kan, Anna Mao, Yize Sun, Shuxin Duan, Fangting Wang, Jun Huang, Peng Li, Shengping Clin Transl Med Research Articles BACKGROUND: Cancer‐associated fibroblasts (CAFs) are among the most prominent cells during the desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC). However, CAFs are heterogeneous and the precise origins are not fully elucidated. This study aimed to explore whether monocytes can transdifferentiate into fibroblasts in PDAC and evaluate the clinical significance of this event. METHODS: CD14(+) monocytes were freshly isolated from human peripheral blood. Immunofluorescence, reverse transcription‐quantitative PCR, western blot, flow cytometry and enzyme‐linked immunosorbent assay were used to detect the expression of αSMA, fibronectin, and other relevant molecules. In addition, latex beads with a mean particle size of 2.0 µm were used to assess the phagocytic capacity. Moreover, RNA sequencing (RNA‐seq) was performed to identify the differences induced by H(2)O(2) and the underlying mechanisms. RESULTS: Immunofluorescence identified αSMA and fibroblast‐specific protein 1 expression by tumor‐associated macrophages in PDAC. The in vitro experiment revealed that oxidative stress (H(2)O(2) or radiation) induced monocyte‐to‐myofibroblast transdifferentiation (MMT), as identified by upregulated αSMA expression at both the RNA and protein levels. In addition, compared with freshly isolated monocytes, human monocyte‐derived macrophages increased fibronectin expression. RNA‐seq analysis identified p53 activation and other signatures accompanying this transdifferentiation; however, the p53 stabilizer nutlin‐3 induced αSMA expression through reactive oxygen species generation but not through the p53 transcription/mitochondria‐dependent pathway, whereas the p38 inhibitor SB203580 could partially inhibit αSMA expression. Finally, MMT produced a unique subset of CAFs with reduced phagocytic capacity that could promote the proliferation of pancreatic cancer cells. CONCLUSIONS: Oxidative stress in the tumor microenvironment could induce MMT in PDAC, thus inducing reactive stroma, modulating immunosuppression, and promoting tumor progression. Reducing oxidative stress may be a promising future therapeutic regimen. John Wiley and Sons Inc. 2020-06-04 /pmc/articles/PMC7403727/ /pubmed/32508052 http://dx.doi.org/10.1002/ctm2.41 Text en © 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Huang, Xin
He, Chaobin
Hua, Xin
Kan, Anna
Mao, Yize
Sun, Shuxin
Duan, Fangting
Wang, Jun
Huang, Peng
Li, Shengping
Oxidative stress induces monocyte‐to‐myofibroblast transdifferentiation through p38 in pancreatic ductal adenocarcinoma
title Oxidative stress induces monocyte‐to‐myofibroblast transdifferentiation through p38 in pancreatic ductal adenocarcinoma
title_full Oxidative stress induces monocyte‐to‐myofibroblast transdifferentiation through p38 in pancreatic ductal adenocarcinoma
title_fullStr Oxidative stress induces monocyte‐to‐myofibroblast transdifferentiation through p38 in pancreatic ductal adenocarcinoma
title_full_unstemmed Oxidative stress induces monocyte‐to‐myofibroblast transdifferentiation through p38 in pancreatic ductal adenocarcinoma
title_short Oxidative stress induces monocyte‐to‐myofibroblast transdifferentiation through p38 in pancreatic ductal adenocarcinoma
title_sort oxidative stress induces monocyte‐to‐myofibroblast transdifferentiation through p38 in pancreatic ductal adenocarcinoma
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403727/
https://www.ncbi.nlm.nih.gov/pubmed/32508052
http://dx.doi.org/10.1002/ctm2.41
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