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Serpin E2 promotes breast cancer metastasis by remodeling the tumor matrix and polarizing tumor associated macrophages.

  • Smirnova T Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • Bonapace L Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • MacDonald G Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • Kondo S Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • Wyckoff J Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • Ebersbach H Novartis Institute for Biomedical Research, Basel, Switzerland.
  • Fayard B Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • Doelemeyer A Novartis Institute for Biomedical Research, Basel, Switzerland.
  • Coissieux MM Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • Heideman MR Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • Bentires-Alj M Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • Hynes NE Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
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  • 2016-10-30
Published in:
  • Oncotarget. - 2016
breast cancer
collagen I
metastasis
serine protease inhibitors
tumor associated macrophages
Animals
Antineoplastic Agents
Breast Neoplasms
Cell Line, Tumor
Cell Movement
Chemokine CCL2
Collagen Type I
Extracellular Matrix
Extracellular Signal-Regulated MAP Kinases
Female
Humans
Lung Neoplasms
Macrophages
Mice, Inbred BALB C
Mice, SCID
Neoplasm Invasiveness
Phenotype
RNA Interference
Serpin E2
Signal Transduction
Tissue Inhibitor of Metalloproteinase-1
Transfection
Tumor Microenvironment
Xenograft Model Antitumor Assays
English The extracellular serine protease inhibitor serpinE2 is overexpressed in breast cancer and has been shown to foster metastatic spread. Here, we investigated the hypothesis that serpinE2 creates tumor-promoting conditions in the tumor microenvironment (TME) by affecting extracellular matrix remodeling. Using two different breast cancer models, we show that blocking serpinE2, either by knock-down (KD) in tumor cells or in response to a serpinE2 binding antibody, decreases metastatic dissemination from primary tumors to the lungs. We demonstrate that in response to serpinE2 KD or antibody treatment there are dramatic changes in the TME. Multiphoton intravital imaging revealed deposition of a dense extracellular collagen I matrix encapsulating serpinE2 KD or antibody-treated tumors. This is accompanied by a reduction in the population of tumor-promoting macrophages, as well as a decrease in chemokine ligand 2, which is known to affect macrophage abundance and polarization. In addition, TIMP-1 secretion is increased, which may directly inhibit matrix metalloproteases critical for collagen degradation in the tumor. In summary, our findings suggest that serpinE2 is required in the extracellular milieu of tumors where it acts in multiple ways to regulate tumor matrix deposition, thereby controlling tumor cell dissemination.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/231706
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