Abstract
The stromal reaction in pancreatic cancer creates a physical barrier that blocks therapeutic intervention and creates an immunosuppressive tumor microenvironment. The Rho/myocardin-related transcription factor (MRTF) pathway is implicated in the hyper-activation of fibroblasts in fibrotic diseases and the activation of pancreatic stellate cells. In this study we use CCG-222740, a small molecule, designed as a Rho/MRTF pathway inhibitor. This compound decreases the activation of stellate cells in vitro and in vivo, by reducing the levels of alpha smooth muscle actin (α-SMA) expression. CCG-222740 also modulates inflammatory components of the pancreas in KC mice (LSL-KrasG12D/+; Pdx-1-Cre) stimulated with caerulein. It decreases the infiltration of macrophages and increases CD4 T cells and B cells. Analysis of the pancreatic adenocarcinoma (PDA) TCGA dataset revealed a correlation between elevated RhoA, RhoC and MRTF expression and decreased survival in PDA patients. Moreover, a MRTF signature is correlated with a Th2 cell signature in human PDA tumors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / metabolism*
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Animals
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Disease Models, Animal
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Female
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Gene Knock-In Techniques
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Homeodomain Proteins / genetics
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Integrases / genetics
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Pancreatic Neoplasms / metabolism*
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Pancreatic Stellate Cells / drug effects*
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Pancreatic Stellate Cells / metabolism
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Proto-Oncogene Proteins p21(ras) / genetics
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RAW 264.7 Cells
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / metabolism
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rhoA GTP-Binding Protein / antagonists & inhibitors*
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rhoA GTP-Binding Protein / metabolism
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rhoC GTP-Binding Protein / antagonists & inhibitors*
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rhoC GTP-Binding Protein / metabolism
Substances
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Homeodomain Proteins
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Mrtfa protein, mouse
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Trans-Activators
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Transcription Factors
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myocardin-related transcription factor B, mouse
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pancreatic and duodenal homeobox 1 protein
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Cre recombinase
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Integrases
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)
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RhoA protein, mouse
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Rhoc protein, mouse
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rhoA GTP-Binding Protein
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rhoC GTP-Binding Protein