Pancreatic fibroblasts smoothen their activities via AKT-GLI2-TGFα

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A Mouse Model to Investigate the Role of Cancer-Associated Fibroblasts in Tumor Growth
06:35

A Mouse Model to Investigate the Role of Cancer-Associated Fibroblasts in Tumor Growth

Published on: December 22, 2020

5.2K

Anil K Rustgi1

  • 1Division of Gastroenterology, Department of Medicine, Department of Genetics, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.

Genes & Development
|September 25, 2016
PubMed

Insights

Depleting Smoothened in pancreatic fibroblasts activates AKT and GLI2, promoting tumor growth. This pathway involves TGFα secretion and EGFR activation, driving pancreatic cancer progression.

Area of Science:

  • Oncology
  • Cell Biology
  • Cancer Research

Background:

  • Pancreatic stromal fibroblasts are crucial components of the tumor microenvironment.
  • Activated fibroblasts play a significant role in supporting tumor growth and progression.

Purpose of the Study:

  • To investigate the role of Smoothened (Smo) signaling in pancreatic stromal fibroblasts.
  • To elucidate the downstream effects of Smo depletion in the pancreatic tumor microenvironment.

Main Methods:

  • Genetic depletion of Smoothened (Smo) in pancreatic stromal fibroblasts.
  • Analysis of signaling pathways including AKT and GLI2.
  • Assessment of TGFα secretion and EGFR activation in pancreatic epithelial cells.

Main Results:

  • Depletion of Smo in pancreatic stromal fibroblasts leads to AKT activation and noncanonical GLI2 activation.
  • This results in increased TGFα secretion, activating EGFR in pancreatic epithelial cells.
  • Smo depletion augments acinar-ductal metaplasia and promotes proliferation of pancreatic tumor cells.

Conclusions:

  • Smoothened signaling in pancreatic fibroblasts is critical for regulating the tumor microenvironment.
  • Targeting Smo-mediated pathways may offer therapeutic strategies for pancreatic cancer.
  • The findings reveal a novel mechanism linking fibroblast signaling to pancreatic cancer development.
Keywords:
AKT signalingEGFR signalingacinar-to-ductal metaplasiahedgehog signalingstromal fibroblast

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