Secretome analysis of patient-derived GBM tumor spheres identifies midkine as a potent therapeutic target

Glioblastoma (GBM) is the most lethal primary brain tumor with few treatment options. The survival of glioma-initiating cells (GICs) is one of the major factors contributing to treatment failure. GICs frequently produce and respond to their own growth factors that support cell proliferation and survival. In this study, we aimed to identify critical autocrine factors mediating GIC survival and to evaluate the anti-GBM effect of antagonizing these factors. Proteomic analysis was performed using conditioned media from two different patient-derived GBM tumor spheres under a growth factor-depleted status. Then, the antitumor effects of inhibiting an identified autocrine factor were evaluated by bioinformatic analysis and molecular validation. Proteins secreted by sphere-forming GICs promote cell proliferation/survival and detoxify reactive oxygen species (ROS). Among these proteins, we focused on midkine (MDK) as a clinically significant and pathologically relevant autocrine factor. Antagonizing MDK reduced the survival of GBM tumor spheres through the promotion of cell cycle arrest and the consequent apoptotic cell death caused by oxidative stress-induced DNA damage. We also identified PCBP4, a novel molecular predictor of resistance to anti-MDK treatment. Collectively, our results indicate that MDK inhibition is an important therapeutic option by suppressing GIC survival through the induction of ROS-mediated cell cycle arrest and apoptosis. Targeting the growth factor midkine (MDK) may offer improved treatment for glioblastoma, the most lethal brain cancer. In glioblastoma, the tumor-initiating cells produce their own growth factors, encouraging themselves to keep multiplying, and making glioblastoma very difficult to treat. Do-Hyun Nam and Hyun Ju Kang at the Samsung Medical Center, Seoul, South Korea and coworkers screened the growth factors produced by two glioblastoma samples, then focused on a single cancer-associated factor, MDK. Antagonizing MDK slowed tumor cell growth, and further investigation showed that suppressing MDK restored the susceptibility of tumor cells to DNA damage and the mechanisms that weed out damaged cells. Noting that treatment efficacy varied between tumor samples, the researchers identified a biomarker for sensitivity to MDK treatment. These results point the way to new treatments for this particularly deadly cancer.