Abstract
Simple SummaryGlioblastoma 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.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.
Highlights
Glioblastomas are the most devastating type of primary brain tumors in adults and are associated with a dismal prognosis of 12 to 14 months survival [1,2]
We found that Lpd and epidermal growth factor receptor (EGFR) mutually co-operate and Lpd interacts with the rapamycin-insensitive companion of mechanistic target of rapamycin kinase (mTOR) (RICTOR) critically co-regulating glioblastoma invasion and radiation sensitivity
We evaluated the function of Lpd for glioblastoma invasiveness using a 3D spheroid invasion assay
Summary
Glioblastomas are the most devastating type of primary brain tumors in adults and are associated with a dismal prognosis of 12 to 14 months survival [1,2]. Treatment of these tumors combines maximal surgical resection and fractionated radiochemotherapy, glioblastomas are associated with high mortality [1,3]. In a Drosophila glial tumor model, the overexpression of Lpd was capable to promote transformation, hyperproliferation and cell invasion of RASv12-induced glial tumor cells In this model, Lpd cooperated with Profilin and serum response factor (SRF) signaling rather than with Ena/VASP and Scar/WAVE proteins to promote oncogenic migration [34]
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