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Verfasst von:Kocher, Daniela [VerfasserIn]   i
 Cao, Lei [VerfasserIn]   i
 Guiho, Romain [VerfasserIn]   i
 Langhammer, Melanie [VerfasserIn]   i
 Lai, Yun-Lu [VerfasserIn]   i
 Becker, Pauline [VerfasserIn]   i
 Hamdi, Hiba [VerfasserIn]   i
 Friedel, Dennis [VerfasserIn]   i
 Selt, Florian [VerfasserIn]   i
 Vonhören, David [VerfasserIn]   i
 Zaman, Julia [VerfasserIn]   i
 Valinciute, Gintvile [VerfasserIn]   i
 Herter, Sonja [VerfasserIn]   i
 Picard, Daniel [VerfasserIn]   i
 Rettenmeier, Johanna [VerfasserIn]   i
 Maaß, Kendra K. [VerfasserIn]   i
 Pajtler, Kristian Wilfried [VerfasserIn]   i
 Remke, Marc [VerfasserIn]   i
 Deimling, Andreas von [VerfasserIn]   i
 Pusch, Stefan [VerfasserIn]   i
 Pfister, Stefan [VerfasserIn]   i
 Oehme, Ina [VerfasserIn]   i
 Jones, David T. W. [VerfasserIn]   i
 Halbach, Sebastian [VerfasserIn]   i
 Brummer, Tilman [VerfasserIn]   i
 Martinez-Barbera, Juan Pedro [VerfasserIn]   i
 Witt, Olaf [VerfasserIn]   i
 Milde, Till [VerfasserIn]   i
 Sigaud, Romain [VerfasserIn]   i
Titel:Rebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines
Verf.angabe:Daniela Kocher, Lei Cao, Romain Guiho, Melanie Langhammer, Yun-Lu Lai, Pauline Becker, Hiba Hamdi, Dennis Friedel, Florian Selt, David Vonhören, Julia Zaman, Gintvile Valinciute, Sonja Herter, Daniel Picard, Johanna Rettenmeier, Kendra K. Maass, Kristian W. Pajtler, Marc Remke, Andreas von Deimling, Stefan Pusch, Stefan M. Pfister, Ina Oehme, David T.W. Jones, Sebastian Halbach, Tilman Brummer, Juan Pedro Martinez-Barbera, Olaf Witt, Till Milde, Romain Sigaud
E-Jahr:2024
Jahr:17 April 2024
Umfang:16 S.
Illustrationen:Illustrationen
Fussnoten:Gesehen am 28.03.2025
Titel Quelle:Enthalten in: Journal of neuro-oncology
Ort Quelle:Dordrecht [u.a.] : Springer Science + Business Media B.V, 1983
Jahr Quelle:2024
Band/Heft Quelle:168(2024), 2 vom: Juni, Seite 317-332
ISSN Quelle:1573-7373
Abstract:INTRODUCTION: Patients with pediatric low-grade gliomas (pLGGs), the most common primary brain tumors in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge. - METHODS: Four patient-derived pediatric glioma models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset (RNA sequencing and LC-MS/MS based phospho-/proteomics) was generated to investigate possible rebound-driving mechanisms. Following in vitro validation, putative rebound-driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model. - RESULTS: Of the tested models, only a BRAFV600E-driven model (BT-40, with additional CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal. Using this model, we identified a rapid reactivation of the MAPK pathway upon MAPKi withdrawal in vitro, also confirmed in vivo. Furthermore, transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels, was observed in vitro. Additionally, we detected increased expression and secretion of cytokines (CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal. While increased cytokine expression did not have tumor cell intrinsic effects, presence of these cytokines in conditioned media led to increased attraction of microglia cells in vitro. - CONCLUSION: Taken together, these data indicate rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound-driving mechanism. Furthermore, increased secretion of microglia-recruiting cytokines may play a role in treatment response and rebound growth upon withdrawal, warranting further evaluation.
DOI:doi:10.1007/s11060-024-04672-9
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

kostenfrei: Volltext: https://doi.org/10.1007/s11060-024-04672-9
 kostenfrei: Volltext: https://link.springer.com/article/10.1007/s11060-024-04672-9
 DOI: https://doi.org/10.1007/s11060-024-04672-9
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:Humans
 Cytokines
 Animals
 Cell Proliferation
 Mice
 Cell Line, Tumor
 Child
 Xenograft Model Antitumor Assays
 Mutation
 Proto-Oncogene Proteins B-raf
 Brain Neoplasms
 Glioma
 Protein Kinase Inhibitors
 Microglia
 MAP Kinase Signaling System
 MAPK inhibitor
 Pediatric low-grade glioma
 Rebound growth
 Treatment withdrawal
 Tumor microenvironment
K10plus-PPN:1920769609
Verknüpfungen:→ Zeitschrift

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