The role of Discoidin Domain Receptors (DDRs) in tumor invasion: a perspective for new therapeutic strategies

High-grade serous ovarian cancer (HG-SOC) is characterized by aggressive metastasis and resistance to chemotherapies. Increased secretion of collagen type I (Col1), the most abundant extracellular matrix protein, correlates with HG-SOC progression and poor patient outcomes. Discoidin Domain Receptors (DDRs) 1 and 2, non-canonical tyrosine kinase receptors (TKRs), are activated by fibrillar collagens and require Src to become fully phosphorylated. In OC, DDR2 sustains invasion, epithelial to mesenchymal transition, and metastasis, acting on both cancer and stromal cell; the molecular mechanisms are not completely understood. In this tumor, β-arrestins (β-arr1 and β-arr2) regulate tumor-stroma communication and oncogenic pathways, including those involving Src, TKRs, and integrins. Their role in DDR2 signaling is completely unknown. Since β-arrs act as allosteric activators of Src, we hypothesize that they interact with DDR2 to regulate its signaling and functional outcomes. To investigate this, we integrated bioinformatic analysis with biochemical and functional assays in HG-SOC cell lines and in human ovarian fibroblasts (HOFs). We found that Col1-activated DDR2 signaling supports tumor cell viability, adhesion, and invasion, while WRG-28, a selective DDR2 inhibitor, impairs DDR2 activation in both tumor and stromal cells, and functional effects in HG-SOC cells. Computational models predicting complexes between DDR2 and β-arr were empirically validated by biochemical assays. Loss/gain function of β-arr1 or β-arr2 demonstrated that β-arrs facilitate DDR2 phosphorylation via Src recruitment. Combined β-arr1 silencing and WRG-28 significantly reduces HG-SOC cell adhesion and invasive behavior. Moreover, in HOFs, nuclear β-arr1 is involved in upregulating ECM-related proteins, and Col1 transcription and secretion, thus amplifying DDR2 activation in cancer cells. Finally, high co-expression of DDR2 and β-arrs correlates with reduced overall (OS) and progression-free survival (PFS) in advanced-stage HG-SOC patients, identifying them as potential markers of disease progression. Our results unveil a novel β-arr/Src-dependent mechanism essential for DDR2 activation and function in HG-SOC. Moreover, stromal β-arr1 might reinforce DDR2 signaling, suggesting that targeting DDR2/β-arr-dependent signaling represents a new approach to simultaneously targeting cancer and stromal cells in this tumor.