TY  - JOUR
AU  - Steinhaeuser, Sophie Sarah
AU  - Morera, Erika
AU  - Budkova, Zuzana
AU  - Schepsky, Alexander
AU  - Wang, Qiong
AU  - Rolfsson, Ottar
AU  - Riedel, Angela
AU  - Krueger, Aileen
AU  - Hilmarsdottir, Bylgja
AU  - Maelandsmo, Gunhild Mari
AU  - Valdimarsdottir, Bryndis
AU  - Sigurdardottir, Anna Karen
AU  - Agnarsson, Bjarni Agnar
AU  - Jonasson, Jon Gunnlaugur
AU  - Ingthorsson, Saevar
AU  - Traustadottir, Gunnhildur Asta
AU  - Oskarsson, Thordur
AU  - Gudjonsson, Thorarinn
TI  - ECM1 secreted by HER2-overexpressing breast cancer cells promotes formation of a vascular niche accelerating cancer cell migration and invasion.
JO  - Laboratory investigation
VL  - 100
IS  - 7
SN  - 1530-0307
CY  - [S.l.]
PB  - Ovid
M1  - DKFZ-2020-00641
SP  - 928-944
PY  - 2020
N1  - 2020 Jul;100(7):928-944
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.
LB  - PUB:(DE-HGF)16
C6  - pmid:32203150
DO  - DOI:10.1038/s41374-020-0415-6
UR  - https://inrepo02.dkfz.de/record/154184
ER  -