(Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
(Samantha Dickson Brain Cancer Unit. UCL Cancer Institute)
(Cancer Immunology Unit. Research Department of Haematology)
| Fecha: |
2023 |
| Resumen: |
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. |
| Ayudas: |
Fundació la Marató de TV3 772/C/2019
Agencia Estatal de Investigación PID2020-115439GB-I00
|
| Nota: |
This work was funded by Cancer Research UK (C55501/A21203, C555011/A22572, C25858/A28592), the Cancer Research UK City of London Centre Award (C7893/A26233), the Radiation Research Unit at the Cancer Research UK City of London Centre Award (C7893/A28990), the NIHR Biomedical Research Centre (BRC507/CN/SP/101330), the Oli Hilsdon Foundation through The Brain Tumour Charity (GN-000595), the MCIN (PID2020-115439GB-I00), and the Fundació la Marató de TV3 (772/C/2019). We thank A. Berns for Cdkn2a−/− mice, M. Aguet for Ifnar1−/− and Ifnar1−/−;Ifngr1−/− mice, P. Salomoni and S. Pollard for constructs, B. Antolin-Fontes for cloning, G. Rodriguez-Esteban for bioinformatics, M. Pathania for technical advice, A. Flanagan for histopathological advice, J. Manji for microscopy, and Y. Guo, G. Morrow, and B. Wilbourn for FACS. Graphical abstract and Figure 2L were created with BioRender.com. Conceptualization, S.P.; methodology, C.G.D. M.C. L.J.B. H.H. S.A.Q. Y.Y. and S.P.; software, E.M. H.H. S.P.C. and Y.Y.; validation, C.G.D. A.P. L.J.B. L.C. and M.C.; formal analysis, C.G.D. E.M. A.P. L.J.B. W.T. G.B. F.G-C, S.P.C. L.C. and F.R.; investigation, C.G.D. M.C. A.P. L.J.B. F.G-C. L.C. and S.R.; resources, H.H. S.A.Q. Y.Y. and S.P.; data curation, E.M. W.T. and G.B.; writing - original draft, C.G.D. M.C. E.M. and S.P.; writing - review & editing, L.J.B. A.P. M.C. S.M. and S.P.; visualization, C.G.D. E.M. A.P. S.P.C. G.B. and S.P.; supervision, H.H. S.A.Q. Y.Y. S.M. and S.P.; project administration, S.P.; funding acquisition, H.H. S.Q. Y.Y. and S.P. H.H. is a co-founder of and equity holder in Omniscope, a scientific advisory board member of MiRXES, and a consultant to Moderna. We support inclusive, diverse, and equitable conduct of research. |
| Nota: |
This work was funded by Cancer Research UK (C55501 / A21203, C555011/A22572, C25858/A28592), the Cancer Research UK City of London Centre Award (C7893 / A26233), the Radiation Research Unit at the Cancer Research UK City of London Centre Award (C7893/A28990), the NIHR Biomedical Research Centre (BRC507 /CN/SP/101330), the Oli Hilsdon Foundation through The Brain Tumour Charity (GN-000595), the MCIN (PID2020-115439GB-I00), and the Fundació la Marató de TV3 (772/C/2019). We thank A. Berns for Cdkn2a −/− mice, M. Aguet for Ifnar1 −/− and Ifnar1 −/− ;Ifngr1 −/− mice, P. Salomoni and S. Pollard for constructs, B. Antolin-Fontes for cloning, G. Rodriguez-Esteban for bioinformatics, M. Pathania for technical advice, A. Flanagan for histopathological advice, J. Manji for microscopy, and Y. Guo, G. Morrow, and B. Wilbourn for FACS. Graphical abstract and Figure 2 L were created with BioRender.com. |
| Derechos: |
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Lengua: |
Anglès |
| Documento: |
Article ; recerca ; Versió publicada |
| Publicado en: |
Cell reports, Vol. 42 Núm. 5 (30 2023) , p. 112472, ISSN 2211-1247 |
visitante ::
identificación
(Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
