Dissecting the role of crosstalk between glioblastoma subpopulations in tumor cell spreading

Maria R Jubran,Sama Tibi,Maxim Mogilevsky,Irina Cojocari,Rotem Karni,Ariel M Rubinstein,Maïté Verreault,Nataly Kravchenko-Balasha,Ahmed Idbaih,Ibukun Adesoji Adejumobi,Ronit V Sionov

doi:10.1038/s41389-020-0199-y

Abstract

Glioblastoma (GBM) is a highly infiltrative brain cancer, which is thus difficult to operate. GBM cells frequently harbor Epidermal Growth Factor Receptor amplification (EGFRwt) and/or activating mutation (EGFRvIII), generating at least two different cellular subpopulations within the tumor. We examined the relationship between the diffusive architectures of GBM tumors and the paracrine interactions between those subpopulations. Our aim was to shed light on what drives GBM cells to reach large cell–cell distances, and whether this characteristic can be manipulated. We established a methodology that quantifies the infiltration abilities of cancer cells through computation of cell–cell separation distance distributions in 3D. We found that aggressive EGFRvIII cells modulate the migration and infiltrative properties of EGFRwt cells. EGFRvIII cells secrete HGF and IL6, leading to enhanced activity of Src protein in EGFRwt cells, and rendering EGFRwt cells higher velocity and augmented ability to spread. Src inhibitor, dasatinib, at low non-toxic concentrations, reduced the infiltrative properties of EGFRvIII/EGFRwt neurospheres. Furthermore, dasatinib treatment induced compact multicellular microstructure packing of EGFRvIII/EGFRwt cells, impairing their ability to spread. Prevention of cellular infiltration or induction of compact microstructures may assist the detection of GBM tumors and tumor remnants in the brains and improve their surgical removal.

Highlights

GBM is an aggressive and highly infiltrative brain cancer that is highly tolerant to anticancer drugs[1,2]
In order to help increase successful therapeutic outcomes a strategy addressing the infiltrative nature of the tumor is highly demanded. To propose such a strategy, we investigated the relationship between the infiltrative nature of GBM tumor cells and the mechanism of interaction between two main GBM cellular subtypes: a cellular subtype harboring mutation in epidermal growth factor receptor (EGFR), EGFRvIII, and a subtype overexpressing wild type EGFR (EGFRwt)
It has been shown that a small subpopulation of EGFRvIII cells within the tumor is responsible for GBM proliferation through cell–cell communication[9]

Summary

Introduction

GBM is an aggressive and highly infiltrative brain cancer that is highly tolerant to anticancer drugs[1,2]. One of the main reasons for poor patient survival is the diffusive nature of. To propose such a strategy, we investigated the relationship between the infiltrative nature of GBM tumor cells and the mechanism of interaction between two main GBM cellular subtypes: a cellular subtype harboring mutation in epidermal growth factor receptor (EGFR), EGFRvIII, and a subtype overexpressing wild type EGFR (EGFRwt). We have recently demonstrated that the diffusive nature of EGFRvIII cells can be mediated by cell–cell homogeneous interactions within the EGFRvIII subpopulation[10]. In the current study we took a step forward by examining the relationship between the diffusive architectures of GBM tumors harboring EGFRvIII mutation and paracrine, heterogeneous interactions between EGFRwt and EGFRvIII cellular subtypes

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