Pré-Publication, Document De Travail Année : 2024

A coregulatory influence map of glioblastoma heterogeneity and plasticity - From cells in vitro to tumors and back again

Chloe Bernhard
  • Fonction : Auteur
Konstantinos Geles
  • Fonction : Auteur
Geoffrey Pawlak
  • Fonction : Auteur
Wajdi Dhifli
  • Fonction : Auteur
Aurelien Dispot
  • Fonction : Auteur
Jules Dusol
  • Fonction : Auteur
Maria Kondratova
  • Fonction : Auteur
Melissa Messe
  • Fonction : Auteur
Damien Reita
  • Fonction : Auteur
David Tulasne
  • Fonction : Auteur
Isabelle Van Seuningen
Natacha Entz-Werle
Silvia-Anna Ciafre
  • Fonction : Auteur

Résumé

We present GBM-cRegMap, an online resource providing a comprehensive coregulatory influence network perspective on glioblastoma (GBM) heterogeneity and plasticity. Using representation learning algorithms, we derived two components of this resource: GBM-CoRegNet, a highly specific coregulatory network of tumor cells, and GBM-CoRegMap, a unified network influence map based on 1612 tumors from 16 studies. As a widely applicable closed-loop system connecting cellular models and tumors, GBM-cRegMap will provide the GBM research community with an easy-to-use web tool (https://gbm.cregmap.com) that maps any existing or newly generated transcriptomic "query" data to a reference coregulatory network and a large-scale manifold of disease heterogeneity. Using GBM-cRegMap, we demonstrated the synergy between the two components by refining the molecular classification of GBM, identifying potential key regulators, and aligning the transcriptional profiles of tumors and in vitro models. Through the amalgamation of a vast dataset, we validated the proneural (PN)-mesenchymal (MES) axis and identified three subclasses of classical (CL) tumors: astrocyte-like (CL-A), epithelial basal-like (CL-B), and cilium-rich (CL-C). We revealed the CL-C subclass, an intermediate state demonstrating the plasticity of GBM cells along the PN-MES axis under chemotherapy. We identified key regulators, such as PAX8, and NKX2.5, involved in TMZ resistance. Notably, NKX2.5, more expressed in higher-grade gliomas, negatively impacts patient survival and regulates genes involved in glucose metabolism.

Dates et versions

hal-04750456 , version 1 (23-10-2024)

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Chloe Bernhard, Konstantinos Geles, Geoffrey Pawlak, Wajdi Dhifli, Aurelien Dispot, et al.. A coregulatory influence map of glioblastoma heterogeneity and plasticity - From cells in vitro to tumors and back again. 2024. ⟨hal-04750456⟩
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