Journal of Neuro-Oncology

, volume 168 , issue 2 , pages 317-332

Rebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines

Daniela Kocher ^{1, 2, 3, 4}

Lei Cao ^{5, 6}

Romain Guiho ^{5, 7}

Melanie Langhammer ^{8, 9}

Yun-Lu Lai ^{1, 2, 3}

Pauline Becker ^{1, 2, 3, 10}

Hiba Hamdi ⁵

Dennis Friedel ^{4, 11, 12}

Florian Selt ^{1, 2, 3, 13}

David Vonhören ^{4, 11, 12}

Julia Zaman ^{4, 11, 12}

Gintvile Valinciute ^{1, 2, 3}

Sonja Herter ^{1, 2, 3, 4}

DANIEL PICARD ^{14, 15, 16}

Johanna Rettenmeier ^{1, 2, 10, 17, 18}

Kendra K Maass ^{1, 2, 17, 18}

Kristian W. Pajtler ^{1, 2, 13, 17, 18}

Marc Remke ¹⁹

Andreas von Deimling ^{11, 12}

Stefan Pusch ^{11, 12}

Stefan M. Pfister ^{1, 2, 13, 17}

Ina Oehme ^{1, 2, 3}

David T W Jones ^{1, 2, 20}

Sebastian Halbach ^{8, 21, 22}

Tilman Brummer ^{8, 21, 23}

Juan Pedro Martinez-Barbera ⁵

Olaf Witt ^{1, 2, 3, 13}

Till Milde ^{1, 2, 3, 13}

Romain Sigaud ^{1, 2, 3}

Hide authors affiliations Show authors affiliations: 23 affiliations

Hopp Children’S Cancer Center Heidelberg (KiTZ), Heidelberg, Germany |

National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany

University Hospital Heidelberg

German Cancer Research Center

German Cancer Research Center (DKFZ) Heidelberg, Clinical Cooperation Unit Pediatric Oncology, Heidelberg, Germany |

⁴

Faculty of Biosciences, Heidelberg University, Heidelberg, Germany |

⁵

Developmental Biology and Cancer Programme, Birth Defects Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK |

⁶

Department of neurosurgery, Beijing tiantan hospital, capital medical university, Beijing, China |

⁷

Nantes Université, Oniris, INSERM, Regenerative Medicine and Skeleton, RMeS, F-44000 Nantes, France

University of Nantes

French Institute of Health and Medical Research

⁸

Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Freiburg, Germany |

⁹

Faculty of Biology, University of Freiburg, Freiburg, Germany |

¹⁰

Faculty of Medicine, Heidelberg University, Heidelberg, Germany |

¹¹

Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany |

¹²

German Cancer Research Center (DKFZ), Clinical Cooperation Unit Neuropathology, Heidelberg, Germany |

¹³

KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany |

¹⁴

Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany |

¹⁵

German cancer consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany |

¹⁶

Institute of Neuropathology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany |

¹⁷

German Cancer Research Center (DKFZ), Division of Pediatric Neurooncology, Heidelberg, Germany |

¹⁸

Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany |

¹⁹

Pediatric Hematology and Oncology, University Children’s Hospital, Saarland University, Homburg, Germany |

²⁰

German Cancer Research Center (DKFZ) Heidelberg, Division of Pediatric Glioma Research, Heidelberg, Germany |

²¹

German Consortium for Translational Cancer Research (DKTK), Freiburg, Germany, German Cancer Research Center (DKFZ), Heidelberg, Germany |

²²

German Cancer Research Center (dkfz), Heidelberg, Germany |

²³

Centre for Biological Signaling Studies BIOSS, University of Freiburg, Freiburg, Germany |

Publication type: Journal Article

Publication date: 2024-04-17

Springer Nature

Journal of Neuro-Oncology

scimago Q1

wos Q2

SJR: 1.139

CiteScore: 6.1

Impact factor: 3.1

ISSN: 0167594X, 15737373

DOI: 10.1007/s11060-024-04672-9

Copy DOI

PubMed ID: 38630384

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 BRAF^V600E-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.

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Kocher D. et al. Rebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines // Journal of Neuro-Oncology. 2024. Vol. 168. No. 2. pp. 317-332.

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@article{2024_Kocher,

author = {Daniela Kocher and Lei Cao and Romain Guiho and Melanie Langhammer and Yun-Lu Lai and Pauline Becker and Hiba Hamdi and Dennis Friedel and Florian Selt and David Vonhören and Julia Zaman and Gintvile Valinciute and Sonja Herter and DANIEL PICARD and Johanna Rettenmeier and Kendra K Maass and Kristian W. Pajtler and Marc Remke and Andreas von Deimling and Stefan Pusch and Stefan M. Pfister and Ina Oehme and David T W Jones and Sebastian Halbach and Tilman Brummer and Juan Pedro Martinez-Barbera and Olaf Witt and Till Milde and Romain Sigaud and others},

title = {Rebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines},

journal = {Journal of Neuro-Oncology},

year = {2024},

volume = {168},

publisher = {Springer Nature},

month = {apr},

url = {https://link.springer.com/10.1007/s11060-024-04672-9},

number = {2},

pages = {317--332},

doi = {10.1007/s11060-024-04672-9}

}

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MLA Copy

Kocher, Daniela, et al. “Rebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines.” Journal of Neuro-Oncology, vol. 168, no. 2, Apr. 2024, pp. 317-332. https://link.springer.com/10.1007/s11060-024-04672-9.

Publisher

Springer Nature

Journal

Journal of Neuro-Oncology

scimago Q1

wos Q2

SJR

1.139

CiteScore

6.1

Impact factor

3.1

ISSN

0167594X (Print)

15737373 (Electronic)