Exploring Glioblastoma intra-tumor heterogeneity through microenvironment cell-cell interactions

Introduction

Glioblastoma (GBM) is the most aggressive and common brain cancer, known for its various sources of heterogeneity. The intra-tumor heterogeneity of GBM can be described by the existence of a limited set of meta-programs, or expression states, that occur in the malignant cells of GBMs. The frequency of each state in a given GBM is influenced by a plasticity between the states and by different genetic drivers. However, the mechanism by which this plasticity occurs remains mostly unknown.

Materials and methods

We profiled several recently-derived GBM cell lines and a mouse model of GBM with scRNA-seq in order to find model systems that recapitulate the diversity of the cellular states observed in our cohort of GBM patient samples. Marker genes for each state enable us to isolate distinct state populations from these models by flow cytometry, in order to explore the cellular states’ plasticity experimentally.

Results and discussion

We show that macrophages can influence the cellular state distributions in our GBM model systems both in vitro and in vivo and identify a specific macrophage-secreted cytokine that mediates this interaction. To further understand the interaction between the GBM states and macrophages, we used computational analyses of scRNA-seq data of human GBM, through which we identified a unique macrophage phenotype associated with GBM.

Conclusion

The cellular states and the transitions between them are crucial to understanding the intra-tumor heterogeneity of Glioblastoma. By combining computational analyses of scRNA-seq data from GBM patient samples with experimental methods in model systems of GBM, we explore the effect of microenvironment cell-cell interactions on the GBM state plasticity. Our findings identify macrophages as an important factor on the cellular state distribution of GBM and set us on a path that can improve the therapeutic outcome of this fatal disease.