Cargando…

The Rho/MRTF pathway inhibitor CCG-222740 reduces stellate cell activation and modulates immune cell populations in Kras(G12D); Pdx1-Cre (KC) mice

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 a...

Descripción completa

Detalles Bibliográficos
Autores principales: Leal, Ana S., Misek, Sean A., Lisabeth, Erika M., Neubig, Richard R., Liby, Karen T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506531/
https://www.ncbi.nlm.nih.gov/pubmed/31068602
http://dx.doi.org/10.1038/s41598-019-43430-0
Descripción
Sumario: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-Kras(G12D/+); 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.