Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics.

in Nature genetics by Avishay Spitzer, Kevin C Johnson, Masashi Nomura, Luciano Garofano, Djamel Nehar-Belaid, Noam Galili Darnell, Alissa C Greenwald, Lillian Bussema, Young Taek Oh, Frederick S Varn, Fulvio D'Angelo, Simon Gritsch, Kevin J Anderson, Simona Migliozzi, L Nicolas Gonzalez Castro, Tamrin Chowdhury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo-Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M Ashley, Stephen T Keir, Keith L Ligon, Jason T Huse, W K Alfred Yung, Anna Lasorella, Antonio Iavarone, Roel G W Verhaak, Itay Tirosh, Mario L Suvà

TLDR

  • This study analyzed matched primary and recurrent GBM samples to understand the evolution of IDH-wildtype GBM after standard-of-care therapy, revealing diverse longitudinal trajectories shaped by treatment and TME modifiers.
  • The findings highlight the importance of considering TME composition and baseline profiles in the development of effective therapeutic strategies for GBM.

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's diverse longitudinal trajectories and highlights the treatment and TME modifiers that shape them.

Overview

  • The study analyzed matched primary and recurrent glioblastoma (GBM) samples from 59 patients to understand the evolution of IDH-wildtype GBM after standard-of-care therapy.
  • The researchers used single-nucleus RNA sequencing and bulk DNA sequencing to assess the longitudinal evolution of the GBM ecosystem across different cellular and molecular heterogeneity layers.
  • The primary objective of the study was to provide a blueprint of GBM's diverse longitudinal trajectories and identify treatment and tumor microenvironment (TME) modifiers that shape them.

Comparative Analysis & Findings

  • The most consistent change observed was a lower malignant cell fraction at recurrence and a corresponding increase in glial and neuronal cell types in the tumor microenvironment (TME).
  • The predominant malignant cell state differed between most matched pairs, with no specific states being exclusive or highly enriched in either time point.
  • However, specific trajectories were enriched in subsets of patients, suggesting that changes in malignant state abundances mirrored changes in TME composition and baseline profiles, reflecting the co-evolution of the GBM ecosystem.

Implications and Future Directions

  • The study provides valuable insights into the treatment and TME modifiers that shape GBM's diverse longitudinal trajectories, which can inform the development of more effective therapeutic strategies.
  • Future studies should aim to validate these findings in larger cohorts and explore the molecular mechanisms underlying the evolution of GBM's diverse trajectories.
  • This research can also inform the design of clinical trials that incorporate TME-targeted therapies to improve treatment outcomes for patients with GBM.
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