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

Sébastien Bougnaud, Anna Golebiewska, Anaïs Oudin, Olivier Keunen, Patrick N. Harter, Lisa Mäder, Francisco Azuaje, Sabrina Fritah, Daniel Stieber, Tony Kaoma, Laurent Vallar, Nicolaas H.C. Brons, Thomas Daubon, Hrvoje Miletic, Terje Sundstrøm, Christel Herold-Mende, Michel Mittelbronn, Rolf Bjerkvig, Simone P. Niclou*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

47 Citations (Scopus)

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 TGFß1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stromaspecific targets that may play a role in combinatorial treatment strategies against glioblastoma.

Original languageEnglish
Pages (from-to)31955-31971
Number of pages17
JournalOncotarget
Volume7
Issue number22
DOIs
Publication statusPublished - 31 May 2016

Keywords

  • Angiogenesis
  • Endothelial cells
  • Glioblastoma
  • Patient-derived xenograft
  • Tumour microenvironment

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