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Cancer-Associated Fibroblasts from Mouse Mammary Tumors as Tools for Molecular and Computational Studies
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Cancer-Associated Fibroblasts from Mouse Mammary Tumors as Tools for Molecular and Computational Studies

Published on: July 3, 2025

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Cancer-associated fibroblasts downregulate type I interferon receptor to stimulate intratumoral stromagenesis

Christina Cho1, Riddhita Mukherjee1, Amy R Peck2

  • 1Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Oncogene
|August 19, 2020
PubMed

Insights

Cancer-associated fibroblasts (CAFs) drive tumor growth by downregulating the type I interferon (IFN1) receptor

Area of Science:

  • Oncology
  • Immunology
  • Cell Biology

Background:

  • Cancer-associated fibroblasts (CAFs) are crucial for solid tumor growth and progression.
  • Desmoplasia, driven by CAFs, involves extracellular matrix (ECM) accumulation.
  • The type I interferon (IFN1) receptor's role in CAF activation and tumor stroma formation is not fully understood.

Purpose of the Study:

  • To investigate the role of IFNAR1, a component of the type I interferon receptor, in CAF activation and tumor stroma formation.
  • To determine the impact of IFNAR1 downregulation on tumor growth in colon and pancreatic ductal adenocarcinoma models.

Main Methods:

  • Utilized Ifnar1 S526A (SA) knock-in mice deficient in IFNAR1 downregulation.
  • Assessed fibroblast activation protein (FAP) expression and ECM accumulation in tumors.
  • Analyzed Smad7 levels in primary fibroblasts and their response to TGFβ.
  • Investigated tumor growth kinetics upon co-injection with wild-type or SA fibroblasts.
  • Examined human colorectal cancer tissues for correlations between IFNAR1 and FAP levels.

Main Results:

  • Tumors in SA mice showed impaired FAP expression and ECM accumulation, indicating deficient stromagenesis.
  • SA fibroblasts exhibited elevated Smad7, a TGFβ pathway inhibitor, which upon knockdown, restored ECM production.
  • Human colorectal cancers displayed an inverse correlation between IFNAR1 and FAP levels.
  • Tumor growth was enhanced by co-injection with wild-type CAFs but not SA CAFs, and fibroblast-specific IFNAR1 ablation accelerated tumor growth.

Conclusions:

  • Downregulation of IFNAR1 in CAFs is essential for efficient stromagenesis and tumor growth.
  • Inactivation of IFNAR1 in CAFs promotes tumor progression by modulating the TGFβ pathway and ECM production.
  • Targeting IFNAR1 in CAFs may represent a novel therapeutic strategy for solid tumors.

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