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.
Highlights
pancreatic stellate cells (PSCs) store lipids in the pancreas and are responsible for the turnover of the extracellular matrix (ECM)[10,11]
Amoeboid movement acquired by cancer cells following remodeling of the extracellular matrix by cancer associated fibroblasts (CAFs) is dependent on the Rho/myocardin-related transcription factor (MRTF) pathway[21,22]
These cells are responsible for chemoresistance and help establish an immunosuppressive tumor microenvironment[2,6]
Summary
PSCs store lipids in the pancreas and are responsible for the turnover of the extracellular matrix (ECM)[10,11]. Through modulation of the actin cytoskeleton, Rho GTPases regulate gene transcription through modulation of myocardin-related transcription factor (MRTF)/ serum response factor (SRF) activity These important signaling GTPases influence cell polarity, microtubule dynamics, membrane transport pathways and transcription factor activity[20]. Altering cytoskeleton-based cell contractility affects cancer cell invasion and modulates interactions between stromal and cancer cells This results in tissue stiffening driving tumor survival, proliferation, and progression. ROCK inhibition with fasudil potentiates gemcitabine response, possibly through modulation of the tumor microenvironment and extracellular matrix composition[21] These findings led us to hypothesize that the Rho/MRTF inhibitor CCG-222740 may be an effective approach to reduce the activation of stellate cells in the pancreas and reduce the formation of fibroinflammatory stroma in the context of pancreatitis in a relevant mouse model for pancreatic cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
