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A Novel Stromal Fibroblast-Modulated 3D Tumor Spheroid Model for Studying Tumor-Stroma Interaction and Drug Discovery
Published on: February 28, 2020
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.
Abstract:
Cancer-associated fibroblasts (CAFs) interact with tumour cells and promote growth and metastasis. Here, we show that CAF activation is reversible: chronic hypoxia deactivates CAFs, resulting in the loss of contractile force, reduced remodelling of the surrounding extracellular matrix and, ultimately, impaired CAF-mediated cancer cell invasion. Hypoxia inhibits prolyl hydroxylase domain protein 2 (PHD2), leading to hypoxia-inducible factor (HIF)-1α stabilisation, reduced expression of αSMA and periostin, and reduced myosin II activity. Loss of PHD2 in CAFs phenocopies the effects of hypoxia, which can be prevented by simultaneous depletion of HIF-1α. Treatment with the PHD inhibitor DMOG in an orthotopic breast cancer model significantly decreases spontaneous metastases to the lungs and liver, associated with decreased tumour stiffness and fibroblast activation. PHD2 depletion in CAFs co-injected with tumour cells similarly prevents CAF-induced metastasis to lungs and liver. Our data argue that reversion of CAFs towards a less active state is possible and could have important clinical implications.
Insights
Chronic hypoxia can reverse cancer-associated fibroblast (CAF) activation, reducing tumour growth and metastasis. This discovery offers potential new therapeutic strategies for cancer treatment.
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.
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