PMID- 32203150
OWN - NLM
STAT- MEDLINE
DCOM- 20201015
LR  - 20230216
IS  - 1530-0307 (Electronic)
IS  - 0023-6837 (Linking)
VI  - 100
IP  - 7
DP  - 2020 Jul
TI  - ECM1 secreted by HER2-overexpressing breast cancer cells promotes formation of a 
      vascular niche accelerating cancer cell migration and invasion.
PG  - 928-944
LID - 10.1038/s41374-020-0415-6 [doi]
AB  - 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.
FAU - Steinhaeuser, Sophie Sarah
AU  - Steinhaeuser SS
AD  - Department of Anatomy, Stem Cell Research Unit, Biomedical Center, Faculty of 
      Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
FAU - Morera, Erika
AU  - Morera E
AD  - Department of Anatomy, Stem Cell Research Unit, Biomedical Center, Faculty of 
      Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
FAU - Budkova, Zuzana
AU  - Budkova Z
AD  - Department of Anatomy, Stem Cell Research Unit, Biomedical Center, Faculty of 
      Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
FAU - Schepsky, Alexander
AU  - Schepsky A
AD  - Department of Anatomy, Stem Cell Research Unit, Biomedical Center, Faculty of 
      Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
FAU - Wang, Qiong
AU  - Wang Q
AD  - Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
FAU - Rolfsson, Ottar
AU  - Rolfsson O
AD  - Center for Systems Biology, University of Iceland, Reykjavik, Iceland.
FAU - Riedel, Angela
AU  - Riedel A
AD  - Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM 
      gGmbH), 69120, Heidelberg, Germany.
AD  - Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120, 
      Heidelberg, Germany.
FAU - Krueger, Aileen
AU  - Krueger A
AD  - Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM 
      gGmbH), 69120, Heidelberg, Germany.
AD  - Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120, 
      Heidelberg, Germany.
FAU - Hilmarsdottir, Bylgja
AU  - Hilmarsdottir B
AD  - Department of Tumor Biology, Institute for Cancer Research, Oslo University 
      Hospital, The Norwegian Radium Hospital, Oslo, Norway.
FAU - Maelandsmo, Gunhild Mari
AU  - Maelandsmo GM
AD  - Department of Tumor Biology, Institute for Cancer Research, Oslo University 
      Hospital, The Norwegian Radium Hospital, Oslo, Norway.
FAU - Valdimarsdottir, Bryndis
AU  - Valdimarsdottir B
AD  - Department of Anatomy, Stem Cell Research Unit, Biomedical Center, Faculty of 
      Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
FAU - Sigurdardottir, Anna Karen
AU  - Sigurdardottir AK
AD  - Department of Anatomy, Stem Cell Research Unit, Biomedical Center, Faculty of 
      Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
FAU - Agnarsson, Bjarni Agnar
AU  - Agnarsson BA
AD  - Department of Pathology, Landspitali-University Hospital, Reykjavik, Iceland.
AD  - Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
FAU - Jonasson, Jon Gunnlaugur
AU  - Jonasson JG
AD  - Department of Pathology, Landspitali-University Hospital, Reykjavik, Iceland.
AD  - Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
FAU - Ingthorsson, Saevar
AU  - Ingthorsson S
AD  - Department of Anatomy, Stem Cell Research Unit, Biomedical Center, Faculty of 
      Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
FAU - Traustadottir, Gunnhildur Asta
AU  - Traustadottir GA
AD  - Department of Anatomy, Stem Cell Research Unit, Biomedical Center, Faculty of 
      Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
FAU - Oskarsson, Thordur
AU  - Oskarsson T
AD  - Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM 
      gGmbH), 69120, Heidelberg, Germany.
AD  - Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120, 
      Heidelberg, Germany.
AD  - German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
FAU - Gudjonsson, Thorarinn
AU  - Gudjonsson T
AD  - Department of Anatomy, Stem Cell Research Unit, Biomedical Center, Faculty of 
      Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 
      tgudjons@hi.is.
AD  - Center for Systems Biology, University of Iceland, Reykjavik, Iceland. 
      tgudjons@hi.is.
AD  - Department of Laboratory Hematology, Landspitali-University Hospital, Reykjavik, 
      Iceland. tgudjons@hi.is.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200318
PL  - United States
TA  - Lab Invest
JT  - Laboratory investigation; a journal of technical methods and pathology
JID - 0376617
RN  - 0 (ECM1 protein, human)
RN  - 0 (Extracellular Matrix Proteins)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
SB  - IM
MH  - Breast Neoplasms/genetics/*metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cell Movement/genetics
MH  - Extracellular Matrix Proteins/genetics/*metabolism
MH  - Female
MH  - Humans
MH  - Neoplasm Invasiveness/*genetics
MH  - Receptor, ErbB-2/genetics/*metabolism
MH  - Tumor Microenvironment/*genetics
EDAT- 2020/03/24 06:00
MHDA- 2020/10/21 06:00
CRDT- 2020/03/24 06:00
PHST- 2019/05/13 00:00 [received]
PHST- 2020/02/26 00:00 [accepted]
PHST- 2020/02/25 00:00 [revised]
PHST- 2020/03/24 06:00 [pubmed]
PHST- 2020/10/21 06:00 [medline]
PHST- 2020/03/24 06:00 [entrez]
AID - S0023-6837(22)00448-2 [pii]
AID - 10.1038/s41374-020-0415-6 [doi]
PST - ppublish
SO  - Lab Invest. 2020 Jul;100(7):928-944. doi: 10.1038/s41374-020-0415-6. Epub 2020 
      Mar 18.