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

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OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 74, PF 41, 01307 Dresden, Germany
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Randall Centre of Cell and Molecular Biophysics, New Hunt’s House, Guy’s Campus, King’s College London, London SE1 1UL, UK
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Institute of Radiooncology-OncoRay, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, 01328 Dresden, Germany
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Department of Radiotherapy and Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, PF 50, 01307 Dresden, Germany
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German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69192 Heidelberg, Germany
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National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69192 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Donat Kögel
Cancers 2021, 13(21), 5337; https://doi.org/10.3390/cancers13215337
Received: 24 November 2020 / Revised: 20 October 2021 / Accepted: 21 October 2021 / Published: 24 October 2021
(This article belongs to the Section Molecular Cancer Biology)
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.
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. View Full-Text
Keywords: Lamellipodin; glioblastoma; invasion; radiosensitivity; RICTOR; EGFR Lamellipodin; glioblastoma; invasion; radiosensitivity; RICTOR; EGFR
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MDPI and ACS Style

Moritz, S.; Krause, M.; Schlatter, J.; Cordes, N.; Vehlow, A. Lamellipodin-RICTOR Signaling Mediates Glioblastoma Cell Invasion and Radiosensitivity Downstream of EGFR. Cancers 2021, 13, 5337. https://doi.org/10.3390/cancers13215337

AMA Style

Moritz S, Krause M, Schlatter J, Cordes N, Vehlow A. Lamellipodin-RICTOR Signaling Mediates Glioblastoma Cell Invasion and Radiosensitivity Downstream of EGFR. Cancers. 2021; 13(21):5337. https://doi.org/10.3390/cancers13215337

Chicago/Turabian Style

Moritz, Stefanie, Matthias Krause, Jessica Schlatter, Nils Cordes, and Anne Vehlow. 2021. "Lamellipodin-RICTOR Signaling Mediates Glioblastoma Cell Invasion and Radiosensitivity Downstream of EGFR" Cancers 13, no. 21: 5337. https://doi.org/10.3390/cancers13215337

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