IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-40235-8.html
   My bibliography  Save this article

MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas

Author

Listed:
  • Romain Sigaud

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT))

  • Thomas K. Albert

    (University Children’s Hospital Münster)

  • Caroline Hess

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University)

  • Thomas Hielscher

    (Division of Biostatistics, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK))

  • Nadine Winkler

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University)

  • Daniela Kocher

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University)

  • Carolin Walter

    (University of Münster)

  • Daniel Münter

    (University Children’s Hospital Münster)

  • Florian Selt

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital)

  • Diren Usta

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital)

  • Jonas Ecker

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital)

  • Angela Brentrup

    (University Hospital Münster)

  • Martin Hasselblatt

    (University Hospital Münster)

  • Christian Thomas

    (University Hospital Münster)

  • Julian Varghese

    (University of Münster)

  • David Capper

    (Berlin Institute of Health
    Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology)

  • Ulrich W. Thomale

    (Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Neurosurgery)

  • Pablo Hernáiz Driever

    (Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German HIT-LOGGIC-Registry for pLGG in children and adolescents, Department of Pediatric Oncology and Hematology)

  • Michèle Simon

    (Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German HIT-LOGGIC-Registry for pLGG in children and adolescents, Department of Pediatric Oncology and Hematology)

  • Svea Horn

    (Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German HIT-LOGGIC-Registry for pLGG in children and adolescents, Department of Pediatric Oncology and Hematology)

  • Nina Annika Herz

    (Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German HIT-LOGGIC-Registry for pLGG in children and adolescents, Department of Pediatric Oncology and Hematology)

  • Arend Koch

    (Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology)

  • Felix Sahm

    (Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Stefan Hamelmann

    (Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Augusto Faria-Andrade

    (McGill University)

  • Nada Jabado

    (McGill University
    McGill University
    McGill University, and The Research Institute of the McGill University Health Centre)

  • Martin U. Schuhmann

    (University Hospital Tübingen)

  • Antoinette Y. N. Schouten-van Meeteren

    (Princess Màxima Center for Pediatric Oncology)

  • Eelco Hoving

    (Princess Màxima Center for Pediatric Oncology)

  • Tilman Brummer

    (University of Freiburg and German Consortium for Translational Cancer Research (DKTK), Freiburg, Germany, German Cancer Research Center (DKFZ))

  • Cornelis M. Tilburg

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital)

  • Stefan M. Pfister

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital
    Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Olaf Witt

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital)

  • David T. W. Jones

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Research Center (DKFZ))

  • Kornelius Kerl

    (University Children’s Hospital Münster)

  • Till Milde

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
    National Center for Tumor Diseases (NCT)
    Heidelberg University Hospital)

Abstract

Pediatric low-grade gliomas (pLGG) show heterogeneous responses to MAPK inhibitors (MAPKi) in clinical trials. Thus, more complex stratification biomarkers are needed to identify patients likely to benefit from MAPKi therapy. Here, we identify MAPK-related genes enriched in MAPKi-sensitive cell lines using the GDSC dataset and apply them to calculate class-specific MAPKi sensitivity scores (MSSs) via single-sample gene set enrichment analysis. The MSSs discriminate MAPKi-sensitive and non-sensitive cells in the GDSC dataset and significantly correlate with response to MAPKi in an independent PDX dataset. The MSSs discern gliomas with varying MAPK alterations and are higher in pLGG compared to other pediatric CNS tumors. Heterogenous MSSs within pLGGs with the same MAPK alteration identify proportions of potentially sensitive patients. The MEKi MSS predicts treatment response in a small set of pLGG patients treated with trametinib. High MSSs correlate with a higher immune cell infiltration, with high expression in the microglia compartment in single-cell RNA sequencing data, while low MSSs correlate with low immune infiltration and increased neuronal score. The MSSs represent predictive tools for the stratification of pLGG patients and should be prospectively validated in clinical trials. Our data supports a role for microglia in the response to MAPKi.

Suggested Citation

  • Romain Sigaud & Thomas K. Albert & Caroline Hess & Thomas Hielscher & Nadine Winkler & Daniela Kocher & Carolin Walter & Daniel Münter & Florian Selt & Diren Usta & Jonas Ecker & Angela Brentrup & Mar, 2023. "MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40235-8
    DOI: 10.1038/s41467-023-40235-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-40235-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-40235-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Zachary J. Reitman & Brenton R. Paolella & Guillaume Bergthold & Kristine Pelton & Sarah Becker & Robert Jones & Claire E. Sinai & Hayley Malkin & Ying Huang & Leslie Grimmet & Zachary T. Herbert & Yu, 2019. "Mitogenic and progenitor gene programmes in single pilocytic astrocytoma cells," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    2. Humsa S. Venkatesh & Wade Morishita & Anna C. Geraghty & Dana Silverbush & Shawn M. Gillespie & Marlene Arzt & Lydia T. Tam & Cedric Espenel & Anitha Ponnuswami & Lijun Ni & Pamelyn J. Woo & Kathryn R, 2019. "Electrical and synaptic integration of glioma into neural circuits," Nature, Nature, vol. 573(7775), pages 539-545, September.
    3. Varun Venkataramani & Dimitar Ivanov Tanev & Christopher Strahle & Alexander Studier-Fischer & Laura Fankhauser & Tobias Kessler & Christoph Körber & Markus Kardorff & Miriam Ratliff & Ruifan Xie & He, 2019. "Glutamatergic synaptic input to glioma cells drives brain tumour progression," Nature, Nature, vol. 573(7775), pages 532-538, September.
    4. Kosuke Yoshihara & Maria Shahmoradgoli & Emmanuel Martínez & Rahulsimham Vegesna & Hoon Kim & Wandaliz Torres-Garcia & Victor Treviño & Hui Shen & Peter W. Laird & Douglas A. Levine & Scott L. Carter , 2013. "Inferring tumour purity and stromal and immune cell admixture from expression data," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
    5. Marta Olah & Vilas Menon & Naomi Habib & Mariko F. Taga & Yiyi Ma & Christina J. Yung & Maria Cimpean & Anthony Khairallah & Guillermo Coronas-Samano & Roman Sankowski & Dominic Grün & Alexandra A. Kr, 2020. "Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Chaitali Chakraborty & Itzel Nissen & Craig A. Vincent & Anna-Carin Hägglund & Andreas Hörnblad & Silvia Remeseiro, 2023. "Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Dylan Scott Lykke Harwood & Vilde Pedersen & Nicolai Schou Bager & Ane Yde Schmidt & Tobias Overlund Stannius & Aušrinė Areškevičiūtė & Knud Josefsen & Dorte Schou Nørøxe & David Scheie & Hannah Rosta, 2024. "Glioblastoma cells increase expression of notch signaling and synaptic genes within infiltrated brain tissue," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Yanming Ren & Zongyao Huang & Lingling Zhou & Peng Xiao & Junwei Song & Ping He & Chuanxing Xie & Ran Zhou & Menghan Li & Xiangqun Dong & Qing Mao & Chao You & Jianguo Xu & Yanhui Liu & Zhigang Lan & , 2023. "Spatial transcriptomics reveals niche-specific enrichment and vulnerabilities of radial glial stem-like cells in malignant gliomas," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. William H. Tomaszewski & Jessica Waibl-Polania & Molly Chakraborty & Jonathan Perera & Jeremy Ratiu & Alexandra Miggelbrink & Donald P. McDonnell & Mustafa Khasraw & David M. Ashley & Peter E. Fecci &, 2022. "Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Ling Hai & Dirk C. Hoffmann & Robin J. Wagener & Daniel D. Azorin & David Hausmann & Ruifan Xie & Magnus-Carsten Huppertz & Julien Hiblot & Philipp Sievers & Sophie Heuer & Jakob Ito & Gina Cebulla & , 2024. "A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1," Nature Communications, Nature, vol. 15(1), pages 1-29, December.
    6. Corina Anastasaki & Juan Mo & Ji-Kang Chen & Jit Chatterjee & Yuan Pan & Suzanne M. Scheaffer & Olivia Cobb & Michelle Monje & Lu Q. Le & David H. Gutmann, 2022. "Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Yuanning Zheng & Francisco Carrillo-Perez & Marija Pizurica & Dieter Henrik Heiland & Olivier Gevaert, 2023. "Spatial cellular architecture predicts prognosis in glioblastoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. Shaoshuai Tang & Yunzhi Wang & Rongkui Luo & Rundong Fang & Yufeng Liu & Hang Xiang & Peng Ran & Yexin Tong & Mingjun Sun & Subei Tan & Wen Huang & Jie Huang & Jiacheng Lv & Ning Xu & Zhenmei Yao & Qi, 2024. "Proteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    9. Lucia Taraborrelli & Yasin Şenbabaoğlu & Lifen Wang & Junghyun Lim & Kerrigan Blake & Noelyn Kljavin & Sarah Gierke & Alexis Scherl & James Ziai & Erin McNamara & Mark Owyong & Shilpa Rao & Aslihan Ka, 2023. "Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    10. Jennifer G. Abelin & Erik J. Bergstrom & Keith D. Rivera & Hannah B. Taylor & Susan Klaeger & Charles Xu & Eva K. Verzani & C. Jackson White & Hilina B. Woldemichael & Maya Virshup & Meagan E. Olive &, 2023. "Workflow enabling deepscale immunopeptidome, proteome, ubiquitylome, phosphoproteome, and acetylome analyses of sample-limited tissues," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    11. Wanzun Lin & Li Chen & Haojiong Zhang & Xianxin Qiu & Qingting Huang & Fangzhu Wan & Ziyu Le & Shikai Geng & Anlan Zhang & Sufang Qiu & Long Chen & Lin Kong & Jiade J. Lu, 2023. "Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    12. Min Kyung Lee & Nasim Azizgolshani & Ze Zhang & Laurent Perreard & Fred W. Kolling & Lananh N. Nguyen & George J. Zanazzi & Lucas A. Salas & Brock C. Christensen, 2024. "Associations in cell type-specific hydroxymethylation and transcriptional alterations of pediatric central nervous system tumors," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    13. Xiaodong Liu & Ke Zhang & Neslihan A. Kaya & Zhe Jia & Dafei Wu & Tingting Chen & Zhiyuan Liu & Sinan Zhu & Axel M. Hillmer & Torsten Wuestefeld & Jin Liu & Yun Shen Chan & Zheng Hu & Liang Ma & Li Ji, 2024. "Tumor phylogeography reveals block-shaped spatial heterogeneity and the mode of evolution in Hepatocellular Carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    14. Alexander Popov & Nadezda Brazhe & Kseniia Morozova & Konstantin Yashin & Maxim Bychkov & Olga Nosova & Oksana Sutyagina & Alexey Brazhe & Evgenia Parshina & Li Li & Igor Medyanik & Dmitry E. Korzhevs, 2023. "Mitochondrial malfunction and atrophy of astrocytes in the aged human cerebral cortex," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    15. Logan Brase & Shih-Feng You & Ricardo D’Oliveira Albanus & Jorge L. Del-Aguila & Yaoyi Dai & Brenna C. Novotny & Carolina Soriano-Tarraga & Taitea Dykstra & Maria Victoria Fernandez & John P. Budde & , 2023. "Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    16. Zheqi Li & Olivia McGinn & Yang Wu & Amir Bahreini & Nolan M. Priedigkeit & Kai Ding & Sayali Onkar & Caleb Lampenfeld & Carol A. Sartorius & Lori Miller & Margaret Rosenzweig & Ofir Cohen & Nikhil Wa, 2022. "ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    17. Yuanyuan Qu & Xiaohui Wu & Aihetaimujiang Anwaier & Jinwen Feng & Wenhao Xu & Xiaoru Pei & Yu Zhu & Yang Liu & Lin Bai & Guojian Yang & Xi Tian & Jiaqi Su & Guo-Hai Shi & Da-Long Cao & Fujiang Xu & Yu, 2022. "Proteogenomic characterization of MiT family translocation renal cell carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    18. Shixiang Wang & Chen-Yi Wu & Ming-Ming He & Jia-Xin Yong & Yan-Xing Chen & Li-Mei Qian & Jin-Ling Zhang & Zhao-Lei Zeng & Rui-Hua Xu & Feng Wang & Qi Zhao, 2024. "Machine learning-based extrachromosomal DNA identification in large-scale cohorts reveals its clinical implications in cancer," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    19. Jiyeon Lee & Julie M. Dimitry & Jong Hee Song & Minsoo Son & Patrick W. Sheehan & Melvin W. King & G. Travis Tabor & Young Ah Goo & Mitchell A. Lazar & Leonard Petrucelli & Erik S. Musiek, 2023. "Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    20. María-Jesús Lobón-Iglesias & Mamy Andrianteranagna & Zhi-Yan Han & Céline Chauvin & Julien Masliah-Planchon & Valeria Manriquez & Arnault Tauziede-Espariat & Sandrina Turczynski & Rachida Bouarich-Bou, 2023. "Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40235-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.