Glioblastoma cell fate is differentially regulated by the microenvironments of the tumor bulk and infiltrative margin
Claudia Garcia-Diaz,
Anni Pöysti,
Elisabetta Mereu,
Melanie P. Clements,
Lucy J. Brooks,
Felipe Galvez-Cancino,
Simon P. Castillo,
Wenhao Tang,
Gordon Beattie,
Lilas Courtot,
Sara Ruiz,
Federico Roncaroli,
Yinyin Yuan,
Samuel Marguerat,
Sergio A. Quezada,
Holger Heyn,
Simona Parrinello
Affiliations
Claudia Garcia-Diaz
Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK
Anni Pöysti
Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK
Elisabetta Mereu
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain
Melanie P. Clements
Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK
Lucy J. Brooks
Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK
Felipe Galvez-Cancino
Cancer Immunology Unit, Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK
Simon P. Castillo
Division of Molecular Pathology & Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
Wenhao Tang
Department of Mathematics, Imperial College London, London, UK
Gordon Beattie
CRUK City of London Centre Single Cell Genomics Facility, UCL Cancer Institute, University College London, London, UK; Genomics Translational Technology Platform, UCL Cancer Institute, University College London, London, UK
Lilas Courtot
Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK
Sara Ruiz
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Federico Roncaroli
Geoffrey Jefferson Brain Research Centre, Division of Neuroscience, School of Biological Sciences, Faculty of Brain and Mental Health, University of Manchester, Manchester, UK
Yinyin Yuan
Division of Molecular Pathology & Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
Samuel Marguerat
Genomics Translational Technology Platform, UCL Cancer Institute, University College London, London, UK
Sergio A. Quezada
Cancer Immunology Unit, Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK
Holger Heyn
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain
Simona Parrinello
Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK; Corresponding author
Summary: Glioblastoma (GBM) recurrence originates from invasive margin cells that escape surgical debulking, but to what extent these cells resemble their bulk counterparts remains unclear. Here, we generated three immunocompetent somatic GBM mouse models, driven by subtype-associated mutations, to compare matched bulk and margin cells. We find that, regardless of mutations, tumors converge on common sets of neural-like cellular states. However, bulk and margin have distinct biology. Injury-like programs associated with immune infiltration dominate in the bulk, leading to the generation of lowly proliferative injured neural progenitor-like cells (iNPCs). iNPCs account for a significant proportion of dormant GBM cells and are induced by interferon signaling within T cell niches. In contrast, developmental-like trajectories are favored within the immune-cold margin microenvironment resulting in differentiation toward invasive astrocyte-like cells. These findings suggest that the regional tumor microenvironment dominantly controls GBM cell fate and biological vulnerabilities identified in the bulk may not extend to the margin residuum.
