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Ryo Yuge, Yasuhiko Kitadai, Hidehiko Takigawa, Toshikatsu Naito, Naohide Oue, Wataru Yasui, Shinji Tanaka, Kazuaki Chayama
Accumulating evidence suggests that a unique set of receptor tyrosine kinases, known as discoidin domain receptors (DDRs), plays a role in cancer progression by interacting with the surrounding collagen matrix. In this study, we investigated the expression and role of DDR1 in human gastric cancer metastasis. Proliferation, migration, invasion, and tube formation assays were conducted in DDR1-expressing MKN74 gastric cancer cells and corresponding DDR1-silenced cells. The effects of DDR1 on tumor growth and metastasis were examined in orthotopically implanted and experimental liver metastasis models in nude mice...
March 13, 2018: Translational Oncology
Nuno M Coelho, Christopher A McCulloch
The preservation of tissue and organ architecture and function depends on tightly regulated interactions of cells with the extracellular matrix (ECM). These interactions are maintained in a dynamic equilibrium that balances intracellular, myosin-generated tension with extracellular resistance conferred by the mechanical properties of the extracellular matrix. Disturbances of this equilibrium can lead to the development of fibrotic lesions that are associated with a wide repertoire of high prevalence diseases including obstructive cardiovascular diseases, muscular dystrophy and cancer...
March 7, 2018: Cell Adhesion & Migration
Chiara Ambrogio, Elodie Darbo, Sam W Lee, David Santamaría
The Discoidin Domain Receptor 1 (DDR1) receptor tyrosine kinase performs pleiotropic functions in the control of cell adhesion, proliferation, survival, migration, and invasion. Aberrant DDR1 function as a consequence of either mutations or increased expression has been associated with various human diseases including cancer. Pharmacological inhibition of DDR1 results in significant therapeutic benefit in several pre-clinical cancer models. Here, we discuss the potential implication of DDR1-dependent pro-survival functions in the development of cancer resistance to chemotherapeutic regimens and speculate on the molecular mechanisms that might mediate such important feature...
March 5, 2018: Cell Adhesion & Migration
Antonino Belfiore, Roberta Malaguarnera, Maria Luisa Nicolosi, Rosamaria Lappano, Marco Ragusa, Andrea Morrione, Veronica Vella
In the last decades increasing importance has been attributed to the Insulin/Insulin-like Growth Factor signaling (IIGFs) in cancer development, progression and resistance to therapy. In fact, IIGFs is often deregulated in cancer. In particular, the mitogenic insulin receptor isoform A (IR-A) and the insulin-like growth factor receptor (IGF-1R) are frequently overexpressed in cancer together with their cognate ligands IGF-1 and IGF-2. Recently, we identified discoidin domain receptor 1 (DDR1) as a new IR-A interacting protein...
February 28, 2018: Cell Adhesion & Migration
Ken Takai, Allison P Drain, Devon A Lawson, Laurie E Littlepage, Marcela Karpuj, Kai Kessenbrock, Annie Le, Kenichi Inoue, Valerie M Weaver, Zena Werb
The discoidin domain receptor 1 (DDR1) is overexpressed in breast carcinoma cells. Low DDR1 expression is associated with worse relapse-free survival, reflecting its controversial role in cancer progression. We detected DDR1 on luminal cells but not on myoepithelial cells of DDR1+/+ mice. We found that DDR1 loss compromises cell adhesion, consistent with data that older DDR1-/- mammary glands had more basal/myoepithelial cells. Basal cells isolated from older mice exerted higher traction forces than the luminal cells, in agreement with increased mammary branches observed in older DDR1-/- mice and higher branching by their isolated organoids...
February 26, 2018: Genes & Development
Hui Jing, Jingyuan Song, Junnian Zheng
Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by various types of collagens that performs a critical role in cell attachment, migration, survival and proliferation. The functions of DDR1 in various types of tumor have been studied extensively. However, in breast carcinoma, the roles of collagen-evoked DDR1 remain ill defined. Although a number of studies have reported that DDR1 promotes apoptosis and inhibits migration in breast carcinoma, it has also been reported to be associated with tumor cell survival, chemoresistance to genotoxic drugs and the facilitation of invasion...
March 2018: Oncology Letters
Aude Dorison, Christos Chantziantoniou
Discoidin Domain Receptor 1 (DDR1) belongs to a family of two non-integrin collagen receptors, DDR1 and DDR2, which display a tyrosine kinase activity. DDR1 has been widely studied in different kind of pathologies including chronic kidney diseases (CKD). The aims of this commentary are 1. to review the existing information about DDR1 expression in healthy and diseased kidney, 2. to comment the data highlighting DDR1 as a major actor in CKD, 3. to suggest areas of research which require further investigation to better characterize the signaling pathways regulating DDR1 role in CKD...
February 19, 2018: Cell Adhesion & Migration
Maya Jeitany, Cédric Leroy, Priscillia Tosti, Marie Lafitte, Jordy Le Guet, Valérie Simon, Debora Bonenfant, Bruno Robert, Fanny Grillet, Caroline Mollevi, Safia El Messaoudi, Amaëlle Otandault, Lucile Canterel-Thouennon, Muriel Busson, Alain R Thierry, Pierre Martineau, Julie Pannequin, Serge Roche, Audrey Sirvent
The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. Here, we show that nilotinib, a clinically approved drug for chronic myeloid leukaemia, strongly inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS-independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1-mediated BCR phosphorylation on Tyr177, which is important for maintaining β-catenin transcriptional activity necessary for tumour cell invasion...
February 9, 2018: EMBO Molecular Medicine
Sooeun Oh, Minkoo Seo, Jun-Sub Choi, Choun-Ki Joo, Suk Kyeong Lee
Discoidin domain receptor 1 (DDR1) is involved in tumorigenesis and angiogenesis. However, its role in lymphangiogenesis has been unknown. Here, we tested whether downregulation of DDR1 expression by miR-199a/b can suppress lymphangiogenesis. We also aimed to identify miRNA target site(s) in the 3' untranslated region (UTR) of DDR1 . Transfection with miR-199a/b-5p mimics reduced expression of DDR1 and tube formation in primary human dermal lymphatic endothelial cells, whereas miR-199a/b-5p inhibitors showed the opposite effects...
February 28, 2018: Molecules and Cells
Huan Bian, Xiaowei Nie, Xin Bu, Feng Tian, Libo Yao, Jingyu Chen, Jin Su
The most typical structural feature of human interstitial lung diseases (ILDs) is the accumulation of vast amounts of collagens within the lung interstitium. The membrane receptors that are responsible for recognising collagens and then transducing signals into the cells include four members of the integrin family (α1β1, α2β1, α10β1 and α11β1) and two members of the discoidin domain receptor family (DDR1 and DDR2). However, it remains unknown whether these six collagen receptors similarly contribute to the pathogenesis of fibrotic lung diseases...
January 2018: ERJ Open Research
Zhiwei Qiao, Kumiko Shiozawa, Tadashi Kondo
Pazopanib, a multitarget tyrosine kinase (TK) inhibitor, has been approved for treatment of soft tissue sarcoma. Elucidation of the molecular background of pazopanib resistance should lead to improved clinical outcomes in sarcomas; accordingly, we investigated this in synovial sarcoma using a proteomic approach. Pazopanib sensitivity was examined in four synovial sarcoma cell lines: SYO-1, HS-SYII, 1273/99, and YaFuSS. The 1273/99 cell line showed significantly higher IC50 values than the others for pazopanib...
December 12, 2017: Oncotarget
Xiujie Sun, Kshama Gupta, Bogang Wu, Deyi Zhang, Bin Yuan, Xiaowen Zhang, Huai-Chin Chiang, Chi Zhang, Tyler J Curiel, Michelle P Bendeck, Stephen Hursting, Yanfen Hu, Rong Li
Discoidin domain receptor 1 (DDR1) is a collagen receptor that mediates cell communications with the extracellular matrix (ECM). Aberrant expression and activity of DDR1 in tumor cells are known to promote tumor growth. Although elevated DDR1 levels in stroma of breast tumors are associated with poor patient outcome, a causal role for tumor-extrinsic DDR1 in cancer promotion remains unclear, however. Here, we report that murine mammary tumor cells transplanted to syngeneic recipient mice in which Ddr1 has been knocked out (KO) grow less robustly than in WT mice...
January 3, 2018: Journal of Biological Chemistry
Diana Vargas-Hurtado, Renata Basto
Centrosome clustering is a process frequently used by cancer cells with extra centrosomes to avoid multipolar divisions. How cell-intrinsic properties influence clustering is not entirely known. In this issue, Rhys et al. (2017. J. Cell Biol. report an unexpected link between clustering capacity and cortical contractility through E-cadherin and DDR1 proteins.
December 19, 2017: Journal of Cell Biology
Zhaofeng Wang, Xianjie Sun, Yi Bao, Juanfen Mo, Hengchao Du, Jichao Hu, Xingen Zhang
In the present study, knockdown of E2F1 impaired the migration and invasion of osteosarcoma cells. Further analysis showed that E2F1 knockdown decreased the expression of discoidin domain receptor 1 (DDR1) which plays a crucial role in many fundamental processes such as cell differentiation, adhesion, migration and invasion. Luciferase and ChIP assays confirmed that E2F1 silencing attenuated the expression of DDR1 through disrupting E2F1-mediated transcription of DDR1 in osteosarcoma cells. Similarly with the effect of E2F1 silencing, DDR1 knockdown weakened the migratory and invasive capabilities of osteosarcoma cells; while overexpression of DDR1 resulted in a significant increase of cell motility and invasiveness, even after knocking down E2F1...
December 2017: International Journal of Oncology
Basavaraj Vastrad, Chanabasayya Vastrad, Ashok Godavarthi, Raghu Chandrashekar
The aim of this study was to identify key genes associated with gliomas and glioblastoma and to explore the related signaling pathways. Gene expression profiles of three glioma stem cell line samples, three normal astrocyte samples, three astrocyte overexpressing 4 iPSC-inducing and oncogenic factors (myc(T58A), OCT-4, p53DD, and H-Ras(G12V)) samples, three astrocyte overexpressing 7 iPSC-inducing and oncogenic factors (OCT4, H-Ras(G12V), myc(T58A), p53DD, cyclin D1, CDK4(RC24) and hTERT) samples and three glioblastoma cell line samples were downloaded from the ArrayExpress database (accession: E-MTAB-4771)...
September 26, 2017: Medical Oncology
Bram Piersma, Olaf Y Wouters, Saskia de Rond, Miriam Boersema, Rutger A F Gjaltema, Ruud A Bank
l-Ascorbic acid (AA), generally known as vitamin C, is a crucial cofactor for a variety of enzymes, including prolyl-3-hydroxylase (P3H), prolyl-4-hydroxylase (P4H), and lysyl hydroxylase (LH)-mediated collagen maturation. Here, we investigated whether AA has additional functions in the regulation of the myofibroblast phenotype, besides its function in collagen biosynthesis. We found that AA positively influences TGFβ1-induced expression of COL1A1, ACTA2, and COL4A1 Moreover, we demonstrated that AA promotes αSMA stress fiber formation as well as the synthesis and deposition of collagens type I and IV Additionally, AA amplified the contractile phenotype of the myofibroblasts, as seen by increased contraction of a 3D collagen lattice...
September 2017: Physiological Reports
Vin Yee Chung, Tuan Zea Tan, Rui-Lan Huang, Hung-Cheng Lai, Ruby Yun-Ju Huang
Epithelial ovarian cancer (EOC) can be stratified according to the stages of epithelial-mesenchymal transition (EMT). Here, we aim to identify tyrosine kinases (TKs) in EOC that correlate with the EMT subtypes. By gene expression microarray, we analyzed the expression levels of tyrosine kinases in EOC cell lines in correlation with EMT. Among the candidate TKs identified, DDR1 was expressed mainly in EOC cells with an Epithelial phenotype. Its expression was validated by qPCR, ELISA and western blotting. Using Infinium HumanMethylation27K BeadChip array and pyrosequencing, we further analyzed the CpG methylation levels at the DDR1 promoter in EOC cells and found that the CpG methylation levels of DDR1 promoter correlated negatively with the expression of DDR1 along the EMT spectrum...
November 30, 2017: Gene
Kristina Y Aguilera, Huocong Huang, Wenting Du, Moriah M Hagopian, Zhen Wang, Stefan Hinz, Tae Hyun Hwang, Huamin Wang, Jason B Fleming, Diego H Castrillon, Xiaomei Ren, Ke Ding, Rolf A Brekken
The extracellular matrix (ECM), a principal component of pancreatic ductal adenocarcinoma (PDA), is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. We found that collagen-induced activation of DDR1 stimulated protumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells...
November 2017: Molecular Cancer Therapeutics
Michaeline Hebron, Margo Peyton, Xiaoguang Liu, Xiaokong Gao, Ruochong Wang, Irina Lonskaya, Charbel E-H Moussa
The role of cell surface tyrosine kinase collagen-activated receptors known as discoidin domain receptors (DDRs) is unknown in neurodegenerative diseases. We detect up-regulation in DDRs level in post-mortem Alzheimer and Parkinson brains. Lentiviral shRNA knockdown of DDR1 and DDR2 reduces the levels of α-synuclein, tau, and β-amyloid and prevents cell loss in vivo and in vitro. DDR1 and DDR2 knockdown alters brain immunity and significantly reduces the level of triggering receptor expressed on myeloid cells (TREM)-2 and microglia...
October 15, 2017: Journal of Neuroimmunology
Yasushi Horimasu, Nobuhisa Ishikawa, Masaya Taniwaki, Kakuhiro Yamaguchi, Kosuke Hamai, Hiroshi Iwamoto, Shinichiro Ohshimo, Hironobu Hamada, Noboru Hattori, Morihito Okada, Koji Arihiro, Yuji Ohtsuki, Nobuoki Kohno
BACKGROUND: Chronic fibrosing idiopathic interstitial pneumonia (IIP) is characterized by alveolar epithelial damage, activation of fibroblast proliferation, and loss of normal pulmonary architecture and function. This study aims to investigate the genetic backgrounds of IIP through gene expression profiling and pathway analysis, and to identify potential biomarkers that can aid in diagnosis and serve as novel therapeutic targets. METHODS: RNA extracted from lung specimens of 12 patients with chronic fibrosing IIP was profiled using Illumina Human WG-6 v3 BeadChips, and Ingenuity Pathway Analysis was performed to identify altered functional and canonical signaling pathways...
August 18, 2017: BMC Medical Genetics
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