Lamellipodin-RICTOR Signaling Mediates Glioblastoma Cell Invasion and Radiosensitivity Downstream of EGFR

SIMPLE SUMMARY: Glioblastoma patients suffer from a poor prognosis with a limited survival of just a few months. Incurability of this tumor mainly results from glioblastoma cell invasiveness as well as therapy resistance. A better understanding of the molecular processes driving aggressive infiltration and resistance to therapeutic intervention would enable the development of new therapeutic approaches. In this study, we identify a so-far-undescribed role of the cytoskeleton protein Lamellipodin in glioblastoma cells. We determined that Lamellipodin essentially mediates glioblastoma invasion, proliferation and radiosensitivity. Our results further identify a new Lamellipodin-RICTOR-EGFR signaling axis enabling glioblastoma radiation survival. ABSTRACT: Glioblastoma is a tumor type of unmet need despite the development of multimodal treatment strategies. The main factors contributing to the poor prognosis of glioblastoma patients are diverse genetic and epigenetic changes driving glioblastoma persistence and recurrence. Complemented are these factors by extracellular cues mediated through cell surface receptors, which further aid in fostering pro-invasion and pro-survival signaling contributing to glioblastoma therapy resistance. The underlying mechanisms conferring this therapy resistance are poorly understood. Here, we show that the cytoskeleton regulator Lamellipodin (Lpd) mediates invasiveness, proliferation and radiosensitivity of glioblastoma cells. Phosphoproteome analysis identified the epidermal growth factor receptor (EGFR) signaling axis commonly hyperactive in glioblastoma to depend on Lpd. Mechanistically, EGFR signaling together with an interaction between Lpd and the Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) jointly regulate glioblastoma radiosensitivity. Collectively, our findings demonstrate an essential function of Lpd in the radiation response and invasiveness of glioblastoma cells. Thus, we uncover a novel Lpd-driven resistance mechanism, which adds an additional critical facet to the complex glioblastoma resistance network.