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A Novel Stromal Fibroblast-Modulated 3D Tumor Spheroid Model for Studying Tumor-Stroma Interaction and Drug Discovery
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Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis.

Chris D Madsen1, Jesper T Pedersen2, Freja A Venning2

  • 1Tumour Cell Biology Laboratory, The Francis Crick Institute (formerly Cancer Research UK London Research Institute), London, UK Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark chris.madsen@bric.ku.dk erik.sahai@crick.ac.uk janine.erler@bric.ku.dk.

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Summary
This summary is machine-generated.

Chronic hypoxia can reverse cancer-associated fibroblast (CAF) activation, reducing tumour growth and metastasis. This discovery offers potential new therapeutic strategies for cancer treatment.

Keywords:
PHD2cancer‐associated fibroblastshypoxiatumour invasion and metastasistumour stiffness

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Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Cancer-associated fibroblasts (CAFs) are key players in tumour progression, promoting cancer cell growth and metastasis.
  • CAF activation involves increased contractile force and extracellular matrix remodeling, contributing to a pro-tumorigenic microenvironment.

Purpose of the Study:

  • To investigate whether CAF activation is a reversible process.
  • To explore the role of chronic hypoxia in modulating CAF phenotype and function.
  • To assess the therapeutic potential of targeting CAF activation in cancer models.

Main Methods:

  • Utilized in vitro and in vivo models of breast cancer.
  • Investigated the effects of chronic hypoxia and PHD2 inhibition on CAF activation markers (αSMA, periostin, myosin II activity).
  • Examined the impact of modulating CAF phenotype on tumour cell invasion and metastasis in orthotopic breast cancer models.

Main Results:

  • Chronic hypoxia was found to deactivate CAFs, leading to reduced contractile force and extracellular matrix remodeling.
  • Hypoxia-induced CAF deactivation was mediated by PHD2 inhibition, HIF-1α stabilization, and decreased expression of αSMA and periostin.
  • Treatment with a PHD inhibitor (DMOG) significantly reduced spontaneous metastases in a breast cancer model.
  • PHD2 depletion in CAFs also prevented CAF-mediated metastasis, highlighting the critical role of PHD2 in CAF activation.

Conclusions:

  • CAF activation is a reversible process, with chronic hypoxia serving as a deactivating factor.
  • Targeting the PHD2-HIF-1α pathway offers a promising strategy to revert CAFs to a less active state.
  • Reversion of CAF phenotype has significant potential for reducing cancer metastasis and improving clinical outcomes.