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Cartilage Oligomeric Matrix Protein initiates cancer stem cells through activation of Jagged1-Notch3 signaling
Konstantinos S. Papadakos a, Michael Bartoschek b, Carmen Rodriguez a, Chrysostomi Gialeli a, Shao-Bo Jin c, Urban Lendahl c, Kristian Pietras b and Anna M. Blom a
a - Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden b - Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden c - Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
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.
The micro-environment surrounding tumor cells typically consist of stromal cells, extracellular matrix (ECM) components, and immune cells, all of which are attracted to and influenced by tumor cells . Tumors consist of heterogenous clones organized in
a complex “community” of cells. Tumors are thus heterogenous clusters of cells and two main models have been proposed to explain this heterogenicity: the stochastic and the cancer stem cell model . According to the cancer stem cell model, tumors
contain a small percentage of cancer stem cells with self-renewing capability that can give rise to sub-clones, which are encountered in a tumor. Cancer stem cells are considered crucial for the progression of tumors as well as for the initiation of metastasis and have therefore been referred to as metastasis-initiating cells .
The core molecular pathways involved in the maintenance and self-renewal of cancer stem cells are Notch, Wnt, and Hedgehog . Notch signaling is a cell-to-cell communication system, initiated when transmembrane ligands (DSL ligands; Delta/Serrate/
108 COMP leads to activation of Notch3
LAG-2) in one cell (the signaling cell) interact with transmembrane Notch receptors on a juxtaposed cell (the signal-receiving cell) . There are four different Notch receptors (1–4), all of which undergo complex proteolytic processing in response to ligand activation. A Notch receptor is produced in the endoplasmic reticulum and subsequently is cleaved by furin-like convertase in the Golgi compartment to form a bipartite protein. The bipartite receptor is comprised of an extracellular portion, which mainly consists of epider-mal growth factor (EGF)-like repeats and an intracel-lular portion, consisting of a transmembrane moiety and a C-terminal domain of a RBP-Jκ-associated module (RAM) domain, ankyrin (ANK) repeats, and nuclear localization signals (NLSs) . Ligand-receptor binding leads to the metalloproteinase-mediated (ADAM10 or ADAM17) cleavage of the Notch extracellular domain which permits further processing of the transmem-brane portion by the γ-secretase complex . The γ-secretase liberates the C-terminal portion of the receptor (the Notch intracellular domain, NICD), which translocates to the nucleus, interacting with the DNA-binding protein CSL (a.k.a RBP-J) and MAML1, which stabilizes the Notch ICD-CSL interaction.