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Glioblastoma cell fate is differentially regulated by the microenvironments of the tumour bulk and infiltrative margin

Garcia-Diaz, Claudia; Mereu, Elisabetta; Clements, Melanie; Pöysti, Anni; Galvez-Cancino, Felipe; Castillo, Simon; Courtot, Lilas; ... Parrinello, Simona; + view all (2021) Glioblastoma cell fate is differentially regulated by the microenvironments of the tumour bulk and infiltrative margin. bioRxiv: Cold Spring Harbor, NY, USA. Green open access

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Abstract

Glioblastoma recurrence originates from invasive cells at the tumour margin that escape surgical debulking, but their biology remains poorly understood. Here we generated three somatic mouse models recapitulating the main glioblastoma driver mutations to characterise margin cells. We find that, regardless of genetics, tumours converge on a common set of neural- like cellular states. However, bulk and margin display distinct neurogenic patterns and immune microenvironments. The margin is immune-cold and preferentially follows developmental-like trajectories to produce astrocyte-like cells. In contrast, injury-like programmes dominate in the bulk, are associated with immune infiltration and generate lowly-proliferative injured neural progenitor-like (iNPCs) cells. In vivo label-retention approaches further demonstrate that iNPCs account for a significant proportion of dormant glioblastoma cells and are induced by interferon signalling within T-cell niches. These findings indicate that tumour region is a major determinant of glioblastoma cell fate and therapeutic vulnerabilities identified in bulk may not extend to the margin residuum.

Type: Working / discussion paper
Title: Glioblastoma cell fate is differentially regulated by the microenvironments of the tumour bulk and infiltrative margin
Open access status: An open access version is available from UCL Discovery
DOI: 10.1101/2021.06.11.447915
Publisher version: https://doi.org/10.1101/2021.06.11.447915
Language: English
Additional information: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license (https://creativecommons.org/licenses/by-nc-nd/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10160561
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