Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis.
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.
Tumour 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.
Chris D
CD
Madsen
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
Jesper T
JT
Pedersen
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
Freja A
FA
Venning
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
Lukram Babloo
LB
Singh
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Emad
E
Moeendarbary
Department of Cell and Developmental Biology, University College London, London, UK London Centre for Nanotechnology, University College London, London, UK.
Guillaume
G
Charras
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
Thomas R
TR
Cox
Tumour Cell Biology Laboratory, The Francis Crick Institute (formerly Cancer Research UK London Research Institute), London, UK chris.madsen@bric.ku.dk erik.sahai@crick.ac.uk janine.erler@bric.ku.dk.
Erik
E
Sahai
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.
Janine T
JT
Erler
D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D001940:Breast / Q000166:cytology; D015815:Cell Adhesion Molecules / Q000235:genetics; D015687:Cell Hypoxia; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D024462:Myosin Type II / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009924:Organ Culture Techniques; D017154:Stromal Cells / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000600:Amino Acids, Dicarboxylic; D015815:Cell Adhesion Molecules; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C512835:POSTN protein, human; C490190:EGLN1 protein, human; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D024462:Myosin Type II; C040947:oxalylglycine
PHD2; cancer‐associated fibroblasts; hypoxia; tumour invasion and metastasis; tumour stiffness