Serpin E2 promotes breast cancer metastasis by remodeling the tumor matrix and polarizing tumor associated macrophages
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Tatiana Smirnova1, Laura Bonapace1, Gwen MacDonald1, Shunya Kondo1, Jeffrey Wyckoff1,2, Hilmar Ebersbach3, Bérengère Fayard1, Arno Doelemeyer3, Marie-May Coissieux1, Marinus R. Heideman1, Mohamed Bentires-Alj1 and Nancy E. Hynes1,4
1 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
2 Koch Institute for Integrated Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
3 Novartis Institute for Biomedical Research, Basel, Switzerland
4 University of Basel, Basel, Switzerland
Tatiana Smirnova, email:
Nancy E. Hynes, email:
Keywords: serine protease inhibitors, collagen I, tumor associated macrophages, breast cancer, metastasis
Received: June 16, 2016 Accepted: October 19, 2016 Published: October 26, 2016
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.
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