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Cartilage Oligomeric Matrix Protein initiates cancer stem cells through activation of Jagged1-Notch3 signaling

Author:
  • Konstantinos S. Papadakos
  • Michael Bartoschek
  • Carmen Rodriguez
  • Chrysostomi Gialeli
  • Shao Bo Jin
  • Urban Lendahl
  • Kristian Pietras
  • Anna M. Blom
Publishing year: 2019
Language: English
Pages: 107-121
Publication/Series: Matrix Biology
Volume: 81
Document type: Journal article
Publisher: Elsevier

Abstract english

Cancer stem cell populations are important for the initiation, progression and metastasis of tumors. The mechanisms governing cancer stem cell control are only partially understood, but activation of the Notch3 pathway plays a crucial role in the maintenance of breast cancer stem cells. Expression of Cartilage Oligomeric Matrix Protein (COMP) in breast cancer cells is correlated with poor survival and higher recurrence rates in patients. In this study, we provide in vivo and in vitro evidence that COMP expression increases the proportion of cancer stem cells in breast cancer. Thus, MDA-MB-231 and BT-20 cells expressing COMP formed larger tumorspheres in vivo and in vitro and displayed higher ALDH-activity than cells lacking COMP. Additionally, BT-20 COMP-expressing cells displayed higher expression of CD133 compared with the control cells. Furthermore, among the different Notch receptors, Notch3 is specifically activated in COMP-expressing cells. Mechanistically, activation of Notch3 is mediated by secreted, polymeric COMP, which interacts with both Notch3 and its ligand Jagged1, bridging the receptor and ligand together, enhancing Notch3-specific signaling. COMP-dependent Notch3 activation also leads to cross-talk with β-Catenin and AKT pathways. Using the model of MMTV-PyMT mouse breast tumorigenesis, we observed a decrease in the size of tumors and the amount of cancer stem cells as well as reduced Notch3 activation, in COMP knockout mice in comparison to wild type mice. In conclusion, we reveal a novel molecular mechanism whereby COMP regulates the cancer stem cell population through increasing the interaction between Notch3 and Jagged1, leading to increased activation of Notch3 signaling.

Keywords

  • Cancer and Oncology
  • Medicinal Chemistry
  • Cancer stem cells
  • COMP
  • Notch3
  • β-Catenin

Other

Published
  • Protein Chemistry, Malmö
  • Experimental oncology
  • ISSN: 0945-053X
E-mail: chrysostomi [dot] gialeli [at] med [dot] lu [dot] se

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