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@ARTICLE{Steinhaeuser:154184,
      author       = {S. S. Steinhaeuser and E. Morera and Z. Budkova and A.
                      Schepsky and Q. Wang and O. Rolfsson and A. Riedel$^*$ and
                      A. Krueger$^*$ and B. Hilmarsdottir and G. M. Maelandsmo and
                      B. Valdimarsdottir and A. K. Sigurdardottir and B. A.
                      Agnarsson and J. G. Jonasson and S. Ingthorsson and G. A.
                      Traustadottir and T. Oskarsson$^*$ and T. Gudjonsson},
      title        = {{ECM}1 secreted by {HER}2-overexpressing breast cancer
                      cells promotes formation of a vascular niche accelerating
                      cancer cell migration and invasion.},
      journal      = {Laboratory investigation},
      volume       = {100},
      number       = {7},
      issn         = {1530-0307},
      address      = {[S.l.]},
      publisher    = {Ovid},
      reportid     = {DKFZ-2020-00641},
      pages        = {928-944},
      year         = {2020},
      note         = {2020 Jul;100(7):928-944},
      abstract     = {The tumor microenvironment is increasingly recognized as
                      key player in cancer progression. Investigating heterotypic
                      interactions between cancer cells and their microenvironment
                      is important for understanding how specific cell types
                      support cancer. Forming the vasculature, endothelial cells
                      (ECs) are a prominent cell type in the microenvironment of
                      both normal and neoplastic breast gland. Here, we sought out
                      to analyze epithelial-endothelial cross talk in the breast
                      using isogenic non-tumorigenic vs. tumorigenic breast
                      epithelial cell lines and primary ECs. The cellular model
                      used here consists of D492, a breast epithelial cell line
                      with stem cell properties, and two isogenic D492-derived EMT
                      cell lines, D492M and D492HER2. D492M was generated by
                      endothelial-induced EMT and is non-tumorigenic while
                      D492HER2 is tumorigenic, expressing the ErbB2/HER2 oncogene.
                      To investigate cellular cross talk, we used both conditioned
                      medium (CM) and 2D/3D co-culture systems. Secretome analysis
                      of D492 cell lines was performed using mass spectrometry and
                      candidate knockdown (KD), and overexpression (OE) was done
                      using siRNA and CRISPRi/CRISPRa technology. D492HER2
                      directly enhances endothelial network formation and
                      activates a molecular axis in ECs promoting D492HER2
                      migration and invasion, suggesting an endothelial feedback
                      response. Secretome analysis identified extracellular matrix
                      protein 1 (ECM1) as potential angiogenic inducer in
                      D492HER2. Confirming its involvement, KD of ECM1 reduced the
                      ability of D492HER2-CM to increase endothelial network
                      formation and induce the endothelial feedback, while
                      recombinant ECM1 (rECM1) increased both. Interestingly,
                      NOTCH1 and NOTCH3 expression was upregulated in ECs upon
                      treatment with D492HER2-CM or rECM1 but not by CM from
                      D492HER2 with ECM1 KD. Blocking endothelial NOTCH signaling
                      inhibited the increase in network formation and the ability
                      of ECs to promote D492HER2 migration and invasion. In
                      summary, our data demonstrate that cancer-secreted ECM1
                      induces a NOTCH-mediated endothelial feedback promoting
                      cancer progression by enhancing migration and invasion.
                      Targeting this interaction may provide a novel possibility
                      to improve cancer treatment.},
      cin          = {HD01 / A010 / A014},
      ddc          = {610},
      cid          = {I:(DE-He78)HD01-20160331 / I:(DE-He78)A010-20160331 /
                      I:(DE-He78)A014-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32203150},
      doi          = {10.1038/s41374-020-0415-6},
      url          = {https://inrepo02.dkfz.de/record/154184},
}