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Inhibiting Tumor Fibrosis and Actomyosin through GPCR activation

Lawrence J Dooling1, Dennis E Discher1

  • 1Biophysical Engineering Labs University of Pennsylvania, Philadelphia, PA 19104, USA.

Trends in Cancer
|April 10, 2019
PubMed

Insights

Tamoxifen inhibits pancreatic stellate cell differentiation into cancer-associated myofibroblasts by activating estrogen receptor GPER. This alters the tumor microenvironment, reducing fibrosis and immunosuppression while increasing vascularization.

Area of Science:

  • Oncology
  • Cancer Biology
  • Tumor Microenvironment

Background:

  • Myofibroblasts contribute to desmoplastic stroma in pancreatic ductal adenocarcinoma (PDAC).
  • These cancer-associated myofibroblasts are potential therapeutic targets.
  • Pancreatic stellate cells (PSCs) differentiate into myofibroblasts.

Purpose of the Study:

  • To investigate the role of tamoxifen and G-protein-coupled receptor (GPCR) for estrogen (GPER) in regulating PSC differentiation.
  • To determine the impact of tamoxifen-mediated GPER activation on the tumor microenvironment in PDAC.

Main Methods:

  • Utilized tamoxifen as an estrogen-receptor modulator.
  • Investigated GPER activation pathways.
  • Assessed changes in actomyosin contractility and mechanosensitive signaling.
  • Analyzed the tumor microenvironment for fibrosis, immunosuppression, and vascularization.

Main Results:

  • Tamoxifen inhibits PSC differentiation into myofibroblasts via GPER activation.
  • This inhibition negatively regulates actomyosin contractility.
  • Downstream mechanosensitive signaling pathways are altered.
  • The tumor microenvironment exhibits reduced fibrosis and immunosuppression.
  • Increased vascularization of the tumor microenvironment was observed.

Conclusions:

  • Tamoxifen, through GPER activation, represents a novel therapeutic strategy for PDAC.
  • Modulating the tumor microenvironment by targeting PSC differentiation offers a promising approach.
  • Targeting myofibroblast activation can reprogram the tumor microenvironment for better therapeutic outcomes.

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