The Rho/MRTF pathway inhibitor CCG-222740 reduces stellate cell activation and modulates immune cell populations in KrasG12D; Pdx1-Cre (KC) mice

Sci Rep. 2019 May 8;9(1):7072. doi: 10.1038/s41598-019-43430-0.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism*
  • Animals
  • Disease Models, Animal
  • Female
  • Gene Knock-In Techniques
  • Homeodomain Proteins / genetics
  • Integrases / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Stellate Cells / drug effects*
  • Pancreatic Stellate Cells / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • RAW 264.7 Cells
  • Trans-Activators / antagonists & inhibitors*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism
  • rhoA GTP-Binding Protein / antagonists & inhibitors*
  • rhoA GTP-Binding Protein / metabolism
  • rhoC GTP-Binding Protein / antagonists & inhibitors*
  • rhoC GTP-Binding Protein / metabolism

Substances

  • Homeodomain Proteins
  • Mrtfa protein, mouse
  • Trans-Activators
  • Transcription Factors
  • myocardin-related transcription factor B, mouse
  • pancreatic and duodenal homeobox 1 protein
  • Cre recombinase
  • Integrases
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • RhoA protein, mouse
  • Rhoc protein, mouse
  • rhoA GTP-Binding Protein
  • rhoC GTP-Binding Protein