TY  - JOUR
A1  - Bougnaud, Sébastien
A1  - Golebiewska, Anna
A1  - Oudin, Anaïs
A1  - Keunen, Olivier
A1  - Harter, Patrick Nikolaus
A1  - Mäder, Lisa
A1  - Azuaje, Francisco
A1  - Fritah, Sabrina
A1  - Stieber, Daniel
A1  - Kaoma, Tony
A1  - Vallar, Laurent
A1  - Brons, Nicolaas H.
A1  - Daubon, Thomas
A1  - Miletic, Hrvoje
A1  - Sundstrøm, Terje
A1  - Herold-Mende, Christel
A1  - Mittelbronn, Michel Guy André
A1  - Bjerkvig, Rolf
A1  - Niclou, Simone P.
T1  - Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma
T2  - OncoTarget
N2  - 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.
KW  - glioblastoma
KW  - patient-derived xenograft
KW  - tumour microenvironment
KW  - endothelial cells
KW  - angiogenesis
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45184
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-451842
SN  - 1949-2553
N1  - All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
VL  - 7
IS  - 22
SP  - 31955
EP  - 31971
PB  - Impact Journals LLC
CY  - [s. l.]
ER  -