@article{92d1c21bf74e488eaa16beafbce7cdc3,
title = "Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics",
abstract = "The evolution of isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. Here we analyzed matched primary and recurrent GBMs from 59 patients using single-nucleus RNA sequencing and bulk DNA sequencing, assessing the longitudinal evolution of the GBM ecosystem across layers of cellular and molecular heterogeneity. The most consistent change was a lower malignant cell fraction at recurrence and a reciprocal increase in glial and neuronal cell types in the tumor microenvironment (TME). The predominant malignant cell state differed between most matched pairs, but no states were exclusive or highly enriched in either time point, nor was there a consistent longitudinal trajectory across the cohort. Nevertheless, specific trajectories were enriched in subsets of patients. Changes in malignant state abundances mirrored changes in TME composition and baseline profiles, reflecting the co-evolution of the GBM ecosystem. Our study provides a blueprint of GBM{\textquoteright}s diverse longitudinal trajectories and highlights the treatment and TME modifiers that shape them.",
keywords = "Humans, Glioblastoma/genetics, Tumor Microenvironment/genetics, Single-Cell Analysis/methods, Brain Neoplasms/genetics, Genomics/methods, Isocitrate Dehydrogenase/genetics, Male, Longitudinal Studies, Female, Neoplasm Recurrence, Local/genetics, Middle Aged",
author = "Avishay Spitzer and Johnson, {Kevin C.} and Masashi Nomura and Luciano Garofano and Djamel Nehar-belaid and Darnell, {Noam Galili} and Greenwald, {Alissa C.} and Lillian Bussema and Oh, {Young Taek} and Varn, {Frederick S.} and Fulvio D{\textquoteright}Angelo and Simon Gritsch and Anderson, {Kevin J.} and Simona Migliozzi and {Gonzalez Castro}, {L. Nicolas} and Tamrin Chowdhury and Nicolas Robine and Catherine Reeves and Park, {Jong Bae} and Anuja Lipsa and Frank Hertel and Anna Golebiewska and Niclou, {Simone P.} and Labeeba Nusrat and Sorcha Kellet and Sunit Das and Moon, {Hyo Eun} and Paek, {Sun Ha} and Franck Bielle and Alice Laurenge and {Di Stefano}, {Anna Luisa} and Bertrand Mathon and Alberto Picca and Marc Sanson and Shota Tanaka and Nobuhito Saito and Ashley, {David M.} and Keir, {Stephen T.} and Ligon, {Keith L.} and Huse, {Jason T.} and Yung, {W. K.Alfred} and Anna Lasorella and Antonio Iavarone and Verhaak, {Roel G.W.} and Itay Tirosh and Suv{\`a}, {Mario L.}",
note = "Funding: M.L.S. is supported by the GBM CARE grant (supplemented to P30 CA006516-56S6), NIH–NCI grants (R01CA276765, R37CA245523, R01CA258763 and P50CA165962), the Mark Foundation Emerging Leader Award, the MGH Research Scholars Award, the Sontag Foundation Distinguished Scientist Alumni Award and the National Foundation for Cancer Research. I.T. is supported by an ERC consolidator grant (101044318), the Zuckerman STEM Leadership Program and the Mexican Friends New Generation grant and is the incumbent of the Dr. Celia Zwillenberg-Fridman and Dr. Lutz Zwillenberg Career Development Chair. A.I. is supported by NIH grants (R35CA253183, P30CA013696- 46S1 and P30CA240139). R.G.W.V. is supported by NIH grants R01CA237208, R21NS114873, R21CA256575 and P30CA034196. A. Lasorella is supported by NIH grants (R01CA268592, R01CA280560 and R01CA239721). M.N. is supported by the Japan Society for the Promotion of Science Overseas Research Fellowship from the Japan Society for the Promotion of Science and an Overseas Research Fellowship from the Uehara Memorial Foundation. A.S. is partially supported by the Israeli Council for Higher Education via the Weizmann Data Science Research Center. A. Lipsa, A.G. and S.P.N. are supported by the Luxembourg National Research Fund and TRANSCAN3 grants (C20/BM/14646004/GLASSLUX and INTER/ TRANSCAN22/17612718/PLASTIG). L.N.G.C. has received honoraria from Elsevier, BMJ Best Practice, Oakstone Publishing and Servier, as well as research support from Merck & Co., Conquer Cancer (the American Society of Clinical Oncology Foundation), the Robert Wood Johnson Foundation and the National Cancer Institute. We thank the PROACTIVE team at MD Anderson for their assistance in procuring patient material. We gratefully acknowledge the contribution of the Jackson Laboratory Single Cell Biology service, S. Bessonett, in particular, the Genome Technologies service and Cyberinfrastructure high-performance computing resources at the Jackson Laboratory for expert assistance related to processing NORLUX/SNU samples and data analysis. These shared services are supported in part by the Jackson Laboratory Cancer Center (P30CA034196). {\textcopyright} 2025. The Author(s).",
year = "2025",
month = may,
day = "9",
doi = "10.1038/s41588-025-02168-4",
language = "English",
volume = "57",
pages = "1168--1178",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Research",
number = "5",
}