Intravital imaging of glioma border morphology reveals distinctive cellular dynamics and contribution to tumor cell invasion

Abstract

The pathogenesis of glioblastoma (GBM) is characterized by highly invasive behavior allowing dissemination and progression. A conclusive image of the invasive process is not available. The aim of this work was to study invasion dynamics in GBM using an innovative in vivo imaging approach. Primary brain tumor initiating cell lines from IDH-wild type GBM stably expressing H2B-Dendra2 were implanted orthotopically in the brains of SCID mice. Using high-resolution time-lapse intravital imaging, tumor cell migration in the tumor core, border and invasive front was recorded. Tumor cell dynamics at different border configurations were analyzed and multivariate linear modelling of tumor cell spreading was performed. We found tumor border configurations, recapitulating human tumor border morphologies. Not only tumor borders but also the tumor core was composed of highly dynamic cells, with no clear correlation to the ability to spread into the brain. Two types of border configurations contributed to tumor cell spreading through distinct invasion patterns: an invasive margin that executes slow but directed invasion, and a diffuse infiltration margin with fast but less directed movement. By providing a more detailed view on glioma invasion patterns, our study may improve accuracy of prognosis and serve as a basis for personalized therapeutic approaches.

Tumor cell plasticity, heterogeneity and resistance in crucial microenvironmental niches in glioma

“…The dynamics, fate, and relevance of individual glioma cells in the perivascular niche was revealed for the rst time in this study over weeks and months. In line with previous work investigating tumor cell dynamics in different tumor areas 32 , tumor cell invasion was not restricted to the invasive front but also prevalent in the dense tumor core. Here, we show that these dynamics are characteristic for parenchymal cells, whereas a majority of perivascular cells shows residency, even at the invasive front.…”

Vessel co-option in glioblastoma: emerging insights and opportunities

“…Almost all GBM patients experience tumor recurrence, typically occurring within 1-2 cm of the original tumor border [20]. Indeed, non-proliferating, infiltrating GBM cells [21] move very fast in the surrounding tissue with a velocity of 2 to 6 μm/h in preclinical models [22]. Their migration is characterized by a diffuse, fast, and undirected movement or by a slower, invasive, directional migration [22].…”

“…Indeed, non-proliferating, infiltrating GBM cells [21] move very fast in the surrounding tissue with a velocity of 2 to 6 μm/h in preclinical models [22]. Their migration is characterized by a diffuse, fast, and undirected movement or by a slower, invasive, directional migration [22]. Histologically, GBM cells infiltrate the surrounding tissue through four different invasion pathways: (i) individual-cell migration within the extracellular matrix (diffuse infiltration), (ii) collective invasion of the surrounding tissue, (iii) peri-neuronal satellitosis, and (iv) perivascular migration (also called as vessel co-option) [8,[22][23][24] (Fig.…”

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

“…Next to genomic and transcriptomic approaches, high-resolution imaging will be of specific benefit for studying dynamic invasive behavior at the single-cell level. Intravital imaging, the visualization of single cells in living tissues through imaging windows (128), together with optogenetic tools will allow to characterize the invasive behavior of single cells over time (129,130). As such, insights can be obtained regarding the heterogeneity of invasive tumor cell populations.…”