title: Serpin E2 promotes breast cancer metastasis by remodeling the tumor matrix and polarizing tumor associated macrophages.
abstract: 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.
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors: Tatiana
authors: T
authors: Smirnova
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors: Laura
authors: L
authors: Bonapace
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors: Gwen
authors: G
authors: MacDonald
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors: Shunya
authors: S
authors: Kondo
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.|Koch Institute for Integrated Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors: Jeffrey
authors: J
authors: Wyckoff
authors: Novartis Institute for Biomedical Research, Basel, Switzerland.
authors: Hilmar
authors: H
authors: Ebersbach
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors: Bérengère
authors: B
authors: Fayard
authors: Novartis Institute for Biomedical Research, Basel, Switzerland.
authors: Arno
authors: A
authors: Doelemeyer
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors: Marie-May
authors: MM
authors: Coissieux
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors: Marinus R
authors: MR
authors: Heideman
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors: Mohamed
authors: M
authors: Bentires-Alj
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors: Nancy E
authors: NE
authors: Hynes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control / Q000556:secondary; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D010641:Phenotype; D034622:RNA Interference; D058258:Serpin E2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014162:Transfection; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D024042:Collagen Type I; C545486:SERPINE2 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: breast cancer; collagen I; metastasis; serine protease inhibitors; tumor associated macrophages