The invasion phenotypes of glioblastoma depend on plastic and reprogrammable cell states

Milena Doroszko, Rebecka Stockgard, Irem Uppman, Josephine Heinold, Faidra Voukelatou, Hitesh Bhagavanbhai Mangukiya, Thomas O. Millner, Madeleine Skeppås, Mar Ballester Bravo, Ramy Elgendy, Maria Berglund, Ludmila Elfineh, Cecilia Krona, Soumi Kundu, Katarzyna Koltowska, Silvia Marino, Ida Larsson and Sven Nelander ()
Additional contact information
Milena Doroszko: Uppsala University, Program for Neurooncology and Neurodegeneration
Rebecka Stockgard: Uppsala University, Program for Neurooncology and Neurodegeneration
Irem Uppman: Uppsala University, Program for Neurooncology and Neurodegeneration
Josephine Heinold: Uppsala University, Program for Neurooncology and Neurodegeneration
Faidra Voukelatou: Uppsala University, Program for Neurooncology and Neurodegeneration
Hitesh Bhagavanbhai Mangukiya: Uppsala University, Program for Neurooncology and Neurodegeneration
Thomas O. Millner: Queen Mary University of London
Madeleine Skeppås: Uppsala University, Program for Neurooncology and Neurodegeneration
Mar Ballester Bravo: Uppsala University, Program for Neurooncology and Neurodegeneration
Ramy Elgendy: Uppsala University, Program for Neurooncology and Neurodegeneration
Maria Berglund: Uppsala University, Program for Neurooncology and Neurodegeneration
Ludmila Elfineh: Uppsala University, Program for Neurooncology and Neurodegeneration
Cecilia Krona: Uppsala University, Program for Neurooncology and Neurodegeneration
Soumi Kundu: Uppsala University, Program for Neurooncology and Neurodegeneration
Katarzyna Koltowska: Uppsala University, Beijer Gene and Neuro Laboratory
Silvia Marino: Queen Mary University of London
Ida Larsson: Uppsala University, Program for Neurooncology and Neurodegeneration
Sven Nelander: Uppsala University, Program for Neurooncology and Neurodegeneration

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Glioblastoma (GBM) is the most common primary brain cancer. It causes death mainly by local invasion via several routes, including infiltration of white matter tracts and penetration of perivascular spaces. However, the pathways that mediate these invasion routes are only partly known. Here, we conduct an integrative study to identify cell states and central drivers of route-specific invasion in GBM. Combining single-cell profiling and spatial protein detection in patient-derived xenograft models and clinical tumor samples, we demonstrate a close association between the differentiation state of GBM cells and their choice of invasion route. Computational modeling identifies ANXA1 as a driver of perivascular involvement in GBM cells with mesenchymal differentiation and the transcription factors RFX4 and HOPX as orchestrators of growth and differentiation in diffusely invading GBM cells. Ablation of these targets in tumor cells alters their invasion route, redistributes the cell states, and extends survival in xenografted mice. Our results define a close association between GBM cell differentiation states and invasion routes, identify functional biomarkers of route-specific invasion, and point toward targeted modulation of specific invasive cell states as a therapeutic strategy in GBM.

Date: 2025
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DOI: 10.1038/s41467-025-61999-1

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