Discoidin Domain Receptor 1 functionally interacts with the IGF-I system in bladder cancer

Abstract

Bladder cancer is one of the most common and aggressive cancers and, regardless of the treatment, often recurs and metastasizes. Thus, a better understanding of the mechanisms regulating urothelial tumorigenesis is critical for the design and implementation of rational therapeutic strategies. We previously discovered that the IGF-IR axis is critical for bladder cancer cell motility and invasion, suggesting a possible role in bladder cancer progression. However, IGF-IR depletion in metastatic bladder cancer cells only partially inhibited anchorage-independent growth. Significantly, metastatic bladder cancer cells have decreased IGF-IR levels but overexpressed the insulin receptor isoform A (IR-A), suggesting that the latter may play a more prevalent role than the IGF-IR in bladder tumor progression. The collagen receptor DDR1 cross-talks with both the IGF-IR and IR in breast cancer, and previous data suggest a role of DDR1 in bladder cancer. Here, we show that DDR1 is expressed in invasive and metastatic, but not in papillary, non-invasive bladder cancer cells. DDR1 is phosphorylated upon stimulation with IGF-I, IGF-II, and insulin, co-precipitates with the IGF-IR, and the IR-A and transient DDR1 depletion severely inhibits IGF-I-induced motility. We further demonstrate that DDR1 interacts with Pyk2 and non-muscle myosin IIA in ligands-dependent fashion, suggesting that it may link the IGF-IR and IR-A to the regulation of F-actin cytoskeleton dynamics. Similarly to the IGF-IR, DDR1 is upregulated in bladder cancer tissues compared to healthy tissue controls. Thus, our findings provide the first characterization of the molecular cross-talk between DDR1 and the IGF-I system and could lead to the identification of novel targets for therapeutic intervention in bladder cancer. Moreover, the expression profiles of IGF-IR, IR-A, DDR1, and downstream effectors could serve as a novel biomarker signature with diagnostic and prognostic significance.