embr.201540107.pdf (1.7 MB)
Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis
journal contributionposted on 2020-08-28, 11:33 authored by Chris D Madsen, Jesper T Pedersen, Freja A Venning, Lukram Babloo Singh, Emad Moeendarbary, Guillaume Charras, Thomas R Cox, Erik Sahai, Janine T Erler
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.
PHD2cancer‐associated fibroblastshypoxiatumour invasion and metastasistumour stiffnessAmino Acids, DicarboxylicAnimalsBreastCell Adhesion MoleculesCell HypoxiaCell MovementFemaleFibroblastsHumansHypoxia-Inducible Factor 1, alpha SubunitHypoxia-Inducible Factor-Proline DioxygenasesMammary Neoplasms, ExperimentalMiceMyosin Type IINeoplasm InvasivenessNeoplasm MetastasisOrgan Culture TechniquesStromal CellsTumor Cells, CulturedSahaiDevelopmental Biology0601 Biochemistry and Cell Biology