Complex roles of discoidin domain receptor tyrosine kinases in cancer

Discoidin domain receptors, DDR1 and DDR2 are members of the receptor tyrosine kinase (RTK) family that serves as a non-integrin collagen receptor and were initially identified as critical regulators of embryonic development and cellular homeostasis. In recent years, numerous studies have focused on the role of these receptors in disease development, in particular, cancer where they have been reported to augment ECM remodeling, invasion, drug resistance to facilitate tumor progression and metastasis. Interestingly, accumulating evidence also suggests that DDRs promote apoptosis and suppress tumor progression in various human cancers due to which their functions in cancer remain ill-defined and presents a case of an interesting therapeutic target. The present review has discussed the role of DDRs in tumorigenesis and the metastasis (AU)

Amplification of DDR2 mediates sorafenib resistance through NF-κB/c-Rel signaling in hepatocellular carcinoma.

Sorafenib was the first systemic therapy approved by the Food and Drug Administration to treat advanced hepatocellular carcinoma (HCC). However, sorafenib therapy is frequently accompanied by drug resistance. We aimed to explore the mechanisms of sorafenib resistance and provide feasible solutions to increase the response to sorafenib in patients with advanced HCC. The expression profile of discoidin domain receptor 2 (DDR2) in HCC tissues and cells was detected using quantitative real-time PCR (qPCR) and western blotting assays. The effects of DDR2 on sorafenib resistance were examined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation, TdT-mediated dUTP nick end labeling, and flow cytometry assays. The effect of DDR2 on the nuclear factor kappa B (NF-κB) signaling pathway was evaluated by luciferase reporter, immunofluorescence, qPCR and flow cytometry assays. We demonstrated that DDR2 expression was dramatically upregulated in sorafenib-resistant HCC tissues relative to sensitive tissues. Downregulation of DDR2 sensitized HCC cell lines to sorafenib cytotoxicity. Further analysis showed that DDR2 could increase the nuclear location of REL proto-oncogene, a NF-κB subunit, to mediate NF-κB signaling. Blocking NF-κB signaling using the NF-κB signaling inhibitor, bardoxolone methyl, increased the response of HCC cells to sorafenib. Further analysis showed that DNA amplification of DDR2 is an important mechanism leading to DDR2 overexpression in HCC. Our results demonstrated that DDR2 is a potential therapeutic target in patients with HCC, and targeting DDR2 represents a promising approach to increase sorafenib sensitivity in patients with HCC.

Complex roles of discoidin domain receptor tyrosine kinases in cancer.

Discoidin domain receptors, DDR1 and DDR2 are members of the receptor tyrosine kinase (RTK) family that serves as a non-integrin collagen receptor and were initially identified as critical regulators of embryonic development and cellular homeostasis. In recent years, numerous studies have focused on the role of these receptors in disease development, in particular, cancer where they have been reported to augment ECM remodeling, invasion, drug resistance to facilitate tumor progression and metastasis. Interestingly, accumulating evidence also suggests that DDRs promote apoptosis and suppress tumor progression in various human cancers due to which their functions in cancer remain ill-defined and presents a case of an interesting therapeutic target. The present review has discussed the role of DDRs in tumorigenesis and the metastasis.

Randomly Distributed K14+ Breast Tumor Cells Polarize to the Leading Edge and Guide Collective Migration in Response to Chemical and Mechanical Environmental Cues.

Collective cell migration is an adaptive, coordinated interactive process involving cell-cell and cell-extracellular matrix (ECM) microenvironmental interactions. A critical aspect of collective migration is the sensing and establishment of directional movement. It has been proposed that a subgroup of cells known as leader cells localize at the front edge of a collectively migrating cluster and are responsible for directing migration. However, it is unknown how and when leader cells arrive at the front edge and what environmental cues dictate leader cell development and behavior. Here, we addressed these questions by combining a microfluidic device design that mimics multiple tumor microenvironmental cues concurrently with biologically relevant primary, heterogeneous tumor cell organoids. Prior to migration, breast tumor leader cells (K14+) were present throughout a tumor organoid and migrated (polarized) to the leading edge in response to biochemical and biomechanical cues. Impairment of either CXCR4 (biochemical responsive) or the collagen receptor DDR2 (biomechanical responsive) abrogated polarization of leader cells and directed collective migration. This work demonstrates that K14+ leader cells utilize both chemical and mechanical cues from the microenvironment to polarize to the leading edge of collectively migrating tumors. SIGNIFICANCE: These findings demonstrate that pre-existing, randomly distributed leader cells within primary tumor organoids use CXCR4 and DDR2 to polarize to the leading edge and direct migration.

Selective Role of Discoidin Domain Receptor 2 in Murine Temporomandibular Joint Development and Aging.

Temporomandibular joint (TMJ) disorders are often associated with development of osteoarthritis-like changes in the mandibular condyle. Discoidin domain receptor 2 (DDR2), a collagen receptor preferentially activated by type I and III collagen found in the TMJ and other fibrocartilages, has been associated with TMJ degeneration, but its role in normal joint development has not been previously examined. Using Ddr2 LacZ-tagged mice and immunohistochemistry, we found that DDR2 is preferentially expressed and activated in the articular zone of TMJs but not knee joints. To assess the requirement for Ddr2 in TMJ development, studies were undertaken to compare wild-type and smallie ( slie) mice, which contain a spontaneous deletion in Ddr2 to produce an effective null allele. Analysis of TMJs from newborn Ddr2slie/slie mice revealed a developmental delay in condyle mineralization, as measured by micro-computed tomography and histologic analysis. In marked contrast, knee joints of Ddr2slie/slie mice were normal. Analysis of older Ddr2slie/slie mice (3 and 10 mo) revealed that the early developmental delay led to a dramatic and progressive loss of TMJ articular integrity and osteoarthritis-like changes. Mutant condyles had a rough and flattened bone surface, accompanied by a dramatic loss of bone mineral density. Mankin scores showed significantly greater degenerative changes in the TMJs of 3- and 10-mo-old Ddr2slie/slie mice as compared with wild-type controls. No DDR2-dependent degenerative changes were seen in knees. Analysis of primary cultures of TMJ articular chondrocytes from wild-type and Ddr2slie/slie mice showed defects in chondrocyte maturation and mineralization in the absence of Ddr2. These studies demonstrate that DDR2 is necessary for normal TMJ condyle development and homeostasis and that these DDR2 functions are restricted to TMJ fibrocartilage and not seen in the hyaline cartilage of the knee.