In conclusion DDR ECD was shown to be
In conclusion, DDR1 ECD was shown to be sufficient for collagen mediated DDR1 oligomerization, and the oligomerized form binds to collagen with increased affinity. In full length receptors expressed on live cells, DDR1 oligomerization occurred on the cell surface in agreement with the role of DDR1 ECD in mediating oligomer formation. Together with our previous observations using a66 expressing DDR1b–YFP (Mihai et al., 2009), that the kinetics of DDR1 oligomerization is very fast (minutes), we propose that the receptor oligomerization precedes its phosphorylation upon collagen stimulation. These insights into receptor oligomerization may help design strategies to modulate DDR1-collagen interaction, receptor function, and downstream signaling.
Introduction Ranked as the seventh most common cancer in women, Epithelial ovarian cancer (EOC) generally has a poor prognosis due to its insidious onset that defy early detection. Most EOC patients are presented at advanced stages and the overall survival merely ranges from 30 to 50% (Ferlay et al., 2015). EOC consists of a heterogeneous entity with distinct histopathological subtypes. The more common subtypes are serous, mucinous, and endometrioid carcinomas; while the less common subtypes include clear cell, transitional, squamous, mixed, and undifferentiated subtype (Hennessy et al., 2009, Silverberg, 1989). Regardless of the different histological subtypes, the treatment for advanced EOC patients remains as the standard surgical debulking followed by taxane/platinum-based chemotherapy (Coleman et al., 2013). This points to the need for better patient stratification based on tumour phenotypes, as well as more targeted, phenotype-specific treatments. By large-scale gene expression profiling, a few studies have classified EOC into different molecular subtypes (Tothill et al., 2008, Cancer Genome Atlas Research Network, 2011, Tan et al., 2013). All three studies identified a mesenchymal subtype in EOC that is associated with an evolutionarily conserved developmental pathway—epithelial-mesenchymal transition (EMT). EMT allows polarized epithelial cells to convert into motile mesenchymal cells through the loss of cell adhesion, which is associated with the downregulation of E-cadherin (Greenburg and Hay, 1982, Thiery, 2002). Apart from its role in normal development, EMT can be utilized by cancer cells to acquire chemoresistance (Kurrey et al., 2009), to maintain their cancer stemness (Mani et al., 2008), and to escape from host immunity (Kudo-Saito et al., 2009). In the recent years, EMT has been implicated in chemotherapy resistance (Helleman et al., 2010) and “migratory cancer stem cell-like” phenotype in recurrent ovarian cancers (Ahmed et al., 2010). Thus, targeting EMT pathways in EOC could be an attractive therapeutic option (Huang et al., 2012). In fact, different stages of EMT involvement may provide a novel way to dissect tumour heterogeneity. Results from gene expression profiling of 42 ovarian cancer cell lines and clinical tumour samples suggested that EOC patients could be stratified according to the epithelial-mesenchymal phenotypes (Huang et al., 2013). By comparing the expression levels of four well-established phenotype markers—E-cadherin, N-cadherin, Cytokeratin, and Vimentin, ovarian tumours are subclassified according to a spectrum of EMT stages. A 33-gene EMT signature was subsequently derived to describe this EMT spectrum (Huang et al., 2013).
Materials and methods
Discussion Discoidin domain receptor (DDR) is a subclass of receptor tyrosine kinases (RTKs) which consists of two members, namely DDR1 and DDR2. Having an extracellular discoidin domain that is homologous to the protein discoidin 1 in Dictyostelium discoideum (Di Marco et al., 1993, Johnson et al., 1993), DDRs are different from other RTKs, as they are not activated by soluble growth factors. Instead, collagens have been identified as their activating ligands (Vogel et al., 1997). Studies have shown that both DDR1 and DDR2 play important roles in cell differentiation, proliferation, adhesion, migration and invasion (Vogel et al., 2006, Leitinger, 2011), and that EMT may involve an expression switch from DDR1 to DDR2 (Maeyama et al., 2008). However, conflicting results have been reported, suggesting that DDR1 could promote (Shintani et al., 2008, Walsh et al., 2011) or suppress EMT (Yeh et al., 2011, Koh et al., 2015). As reviewed by Valiathan et al. and Rammal et al., the regulatory roles (positive or negative) of DDR1 in cancer cell proliferation, migration and invasion has remained controversial and may be tumour type-dependent (Valiathan et al., 2012, Rammal et al., 2016). In breast and ovarian cancer, the expression of DDR1 transcript was reported to be upregulated in tumour cells, at least three folds higher compared to the surrounding normal epithelia (Barker et al., 1995, Heinzelmann-Schwarz et al., 2004, Quan et al., 2011). Consistent with these findings, our results in this study showed that DDR1 was detected in EOC cell lines and tumour samples but not in normal ovarian surface epithelial cells. However, recent findings propose that EOCs may also arise from the fallopian tube fimbriae cells (Dubeau and Drapkin, 2013). The expression of DDR1 in normal fallopian tissues remains to be tested.