Abstract 4415: Discoidin domain receptor 1 (DDR1) and IGF-I system crosstalk in bladder cancer progression
Authors: Morcavallo Alaide , Buraschi Simone , Xu Shi-Qiong , Gomella Leonard G. , Belfiore Antonino , Iozzo Renato V. , Morrione Andrea 
Published: May 2015

Bladder cancer is a major public health problem and affects more than 72,570 Americans with more than 15,000 estimated deaths in 2013. The majority of deaths is due to metastatic spread. Understanding the molecular mechanisms regulating bladder tumor cell invasion and progression toward metastases is essential for developing better therapies to treat bladder cancer patients. The insulin-like growth factor I (IGF-I) system and its two major receptors, the IGF-IR and IR, play a central role in a variety of physiological processes including growth, motility and glucose homeostasis. The IGF-IR is also critical for tumorigenesis through its ability to promote cell growth and protect cancer cells from apoptosis. We have recently shown that the IGF-IR and the Proline-rich tyrosine-kinase 2 (Pyk2) are critical for bladder cancer cell motility and invasion. However, IGF-IR depletion in metastatic bladder cancer cells only partially inhibits anchorage-independent growth. Significantly, metastatic bladder cancer cells have decreased IGF-IR levels but overexpress the IR-A isoform, suggesting that the latter may play a more prevalent role than the IGF-IR in promoting metastasis. It has been recently demonstrated that another receptor tyrosine kinase, the discoidin domain receptor 1 (DDR1) is a substrate for the IR-A. DDR1, the receptor for fibrillar collagens, plays a broad role in adhesion and motility in many cellular models.

Here we show that DDR1 was expressed in invasive and metastatic but not in papillary non-invasive bladder cancer cells. DDR1 was phosphorylated upon stimulation with IGF-I, IGF-II and insulin and co-precipitated with the IGF-IR and the IR-A in invasive and metastatic bladder cancer cells respectively. Significantly, DDR1 depletion severely inhibited IGF-I-induced motility of invasive 5637 cells indicating an essential role of DDR1 in modulating IGF-IR action. Additionally, DDR1 interacted with Pyk2 and non-muscle myosin IIA in ligand-dependent fashion suggesting that DDR1 may modulate IGF-IR and IR-A-dependent bladder cancer cell motility by linking the IGF-IR and IR-A to the regulation of F-actin cytoskeleton dynamics. Furthermore, DDR1 is upregulated in bladder cancer tissues compared to normal tissue controls.

The characterization of the cross-talk between the IGF-I system and DDR1 will greatly contribute to the identification of novel targets for therapeutic intervention in bladder tumors. In addition, the IGF-IR, IR-A, DDR1 and downstream effectors Pyk2 and myosin IIA may serve as novel biomarkers with diagnostic and prognostic significance in bladder cancer.

Citation Format: Alaide Morcavallo, Simone Buraschi, Shi-Qiong Xu, Leonard G. Gomella, Antonino Belfiore, Renato V. Iozzo, Andrea Morrione. Discoidin domain receptor 1 (DDR1) and IGF-I system crosstalk in bladder cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4415. doi:10.1158/1538-7445.AM2014-4415