Discoidin domain receptors DDR1 and DDR2 are the only receptor tyrosine kinases that bind to and signal in response to collagen. In cancer, DDRs have been shown to play a key role in mediating the crosstalk between tumor cells and the stromal collagen matrix. Because prostate cancer (PCa) preferentially metastasizes to bone, a collagen-rich microenvironment, we set out to investigate the role of DDR1 in intraosseous growth of PC3 cells, a human PCa cell line that expresses DDR1 but not DDR2. PC3 cells were engineered to express short hairpin RNAs (shRNAs) against DDR1, or a scrambled shRNA as a control. These cells were inoculated into the tibiae of male SCID mice, and then bone response and intraosseous tumor growth evaluated by X-ray and histomorphometry. Whereas no differences were observed in bone response (osteolytic lesions), downregulation of DDR1 in PC3 cells was associated with a significant increase in intraosseous tumor growth when compared to control PC3 cells (P<0.05, Mann-Whitney test). To further evaluate the role of DDR1 in PC3 tumor growth, human DDR1a was overexpressed in PC3 cells. The engineered cells were inoculated subcutaneously into SCID mice and tumor growth was monitored over time. Tumors formed by DDR1a-overexpressing PC3 cells were significantly smaller than those obtained with control cells (P<0.005, at final time point, Mann-Whitney test). We also evaluated the expression of DDR1 in a 200-case grade/stage tissue microarray (TMA) with matched normal tissue obtained from The Prostate Cancer Biorepository Network (PCBN). Tissues were subjected to immunohistochemistry (IHC) with an antibody to human DDR1. A predominant membranous DDR1 immunostaining was observed in most epithelial prostate cells, with sporadic cytoplasmic or nuclear immunoreactivity. We found no differences in DDR1 expression between normal and benign prostate glands and low-grade PCa (Gleason score ≤7 [3+4]). However, a significantly lower DDR1 expression was observed in high-grade PCa (Gleason score ≥7 [4+3]) when compared to low-grade PCa (P=0.002, Fisher's exact test). These results suggest that reduced DDR1 expression in PCa is associated with a more aggressive disease. Collectively, these data highlight an unreported role of DDR1 in PCa progression whereby DDR1 may elicit a tumor-suppressive activity, as shown by its ability to reduce intraosseous and subcutaneous growth of PC3 cell xenografts. These data also suggest a differential role for DDRs in PCa bone metastasis whereby DDR1, as opposed to DDR2 (as reported previously), restrains intraosseous PCa growth. Because DDRs are being considered as potential novel therapeutic targets in cancer, defining their precise contributions in PCa progression is of critical importance for the development of effective therapies in this cancer type.
Citation Format: R. Daniel Bonfil, Anjum Sohail, Semir Vranić, Daniel S. Oliveira, Dongping Shi, Wei Chen, Hyejeong Jang, Allen D. Saliganan, Benjamin D. Wasinski, Hyeong-Reh C. Kim, Rafael A. Fridman. Discoidin domain receptor 1 (DDR1): A potential suppressor of prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1070.