Tumor heterogeneity and tumor-microglia interactions in primary and recurrent IDH1 mutant gliomas

Key info

Diffuse gliomas harbor recurrent mutations in the isocitrate dehydrogenase (IDH) gene. IDH mutant gliomas are classified into two major subtypes: Oligodendrogliomas with chromosome arms 1p/19q codeletion and astrocytomas with euploid 1p/19q. Recent studies have highlighted intratumoral heterogeneity as a feature of IDH mutant gliomas. These tumors exhibit a hierarchy of cellular phenotypes, with a neural stem cell-like population giving rise to tumor subpopulations with expression signatures resembling astrocytes and oligodendrocytes. However, a detailed comparison of transcriptional and epigenomic heterogeneity in oligodendrogliomas and astrocytomas is still lacking.

In addition, IDH mutant gliomas have distinct activation states of tumor-associated microglia/macrophages (TAMs); however, it is not clear whether TAM composition differs between oligodendrogliomas and astrocytomas, how tumor subpopulations interact with TAMs and to what extent tumor grade and recurrence play a role in promoting TAM diversity in diffuse gliomas. Therefore, comparative analyses of tumor heterogeneity and tumor-stroma interactions are critical to our understanding of IDH mutant gliomas and their evolution.

Here, we performed high-throughput single-nucleus RNA and ATAC sequencing (snRNA- and snATAC-seq) on primary IDH mutant gliomas and snRNA-seq on a cohort of primary and recurrent astrocytoma pairs to create a resource to comprehensively resolve tumor diversity and TAM states. Our results confirm the previously described differentiation hierarchies and reveal a novel group of epigenetically and transcriptionally distinct ribosomal enriched non-cycling stem-like tumor cells in IDH mutant gliomas. We identify significant transcriptional differences in TAM states between oligodendrogliomas and astrocytomas, and receptor-ligand interaction mapping between tumor subpopulations and TAM states reveals a notable interaction between inflammatory TAMs and astrocytic tumor subpopulations in astrocytomas confirmed by immunohistochemical analyses of validation cohorts. These results suggest that TAM-tumor interactions may contribute to the clinical course of oligodendrogliomas and astrocytomas.

Book contents

In the present book, we have compiled all the code used in the analysis and to generate the figures. A couple of notes worth mentioning:

  • Absolute paths are displayed, which will not work on another user’s end.
  • Objects are loaded based on such pathways. Another user will have to regenerate such objects based on the available data.
  • Metadata columns may vary between the code and the available metadata. However, this should be a name change.
  • Some figures might slightly vary from the final version on the paper, due to modifications with Affinity Designer.
  • Development version of SCpubr was used (equivalent to v2.X.X, when published) for the figures.

Contact

Corresponding authors:

  • Sevin Turcan: sevin.turcan@med.uni-heidelberg.de
  • Holger Heyn: holger.heyn@cnag.eu

For any queries on the figures, please contact:

  • Enrique Blanco Carmona: e.blancocarmona@kitz-heidelberg.de
  • If related to SCpubr: https://github.com/enblacar/SCpubr/issues/new/choose