Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma

Abstract

The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFβ1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma.

In vivo characterization of brain metabolism by 1H MRS, 13C MRS and 18FDG PET reveals significant glucose oxidation of invasively growing glioma cells

“…7 The absence of a necrotic core is commonly observed in xenograft models derived from glioma stem-like cells. 1,28 Necrotic regions are often associated with reduced concentrations of Glu and Gln due to neuronal loss and reduced glucose oxidation. However, the direct assessment of Glu and Gln concentration in vivo is quite challenging.…”

DNA repair mechanisms and their clinical impact in glioblastoma

“…Organotypic spheroids formed from patient-derived GBM biopsies better preserve the original tissue architecture, the genomic profile and DNA ploidy of the parental tumor (7,193). Importantly, such spheroids do not undergo passaging and selection in vitro and, instead, can be maintained by serial transplantation in vivo, which maintains the original genetic and phenotypic heterogeneity of the biospy (194). Similarly, GSC sphere cultures partially reiterate the molecular features of the original tumor and we have recently shown that such cell lines establish similar histological phenotypes as organotypic spheroid-based xenografts (194).…”

“…Importantly, such spheroids do not undergo passaging and selection in vitro and, instead, can be maintained by serial transplantation in vivo, which maintains the original genetic and phenotypic heterogeneity of the biospy (194). Similarly, GSC sphere cultures partially reiterate the molecular features of the original tumor and we have recently shown that such cell lines establish similar histological phenotypes as organotypic spheroid-based xenografts (194). Nevertheless, GSC cultures also undergo in vitro selection and changes in DNA ploidy (7).…”

Mesenchymal stem cells differentially affect the invasion of distinct glioblastoma cell lines

“…Communication between stromal cells and GBM cells creates a tumor-promoting environment [19]. Stromal mesenchymal stem cells (MSCs) can induce the transition to a more invasive GBM cell phenotype [20] that shows similarities with epithelial to mesenchymal transition (EMT) or with the mesenchymal to amoeboid transition [21].…”