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P120-catenin dependent glioma-cell networks drive growth and diffuse brain infiltration

ABSTRACT: The poor prognosis of diffuse gliomas is the consequence of adaptive growth and survival programs coupled to their unsurmountable capacity to infiltrate the brain. Diffuse brain infiltration is a particularly detrimental hallmark of gliomas, however the underlying cellular and signaling mechanisms remain elusive. Histological analysis of glioma samples suggests brain invasion by individual glioma cells extending along blood vessels and nerve tracts, consistent with individual-cell growth and invasion programs. However, using thick 3D tissue sections, we here show that human diffuse gliomas consist of multicellular networks in both tumor center and invasion region. This was confirmed in three orthotopic human glioma xenograft models in mouse brain reflecting neuronal, proneural and mesenchymal subtypes. The connections between glioma cells are provided by either branched filamentous protrusions connecting cells across distance or epithelial-like linear adherens junctions between directly adjacent cells. These intercellular contacts showed dynamic turn-over kinetics, which enabled intercellularly synchronized calcium signaling waves, directionally persistent migration as network and network plasticity. Interference with the stability of adherens junction by downregulating p120-catenin causes irreversibly compromised cell-cell interaction, near-complete inhibition of diffuse brain infiltration and a severe growth defect and marginalized microlesions as outcome. Mining of human glioma cohorts revealed an inverse association of p120 with patient survival and, using next-generation RNA sequencing, profound cell reprogramming with perturbed cell adhesion and axonal guidance pathways was uncovered after p120 downregulation. In conclusion, reminiscent of neuronal and glial progenitor programs during morphogenesis and repair, diffuse gliomas progress as neuronal-like, collective network the subunits of which cooperate by complex cell-cell signaling to promote cell growth and detrimental brain infiltration. Targeting adherens junctions and cell-cell cooperation thus represent unanticipated therapeutic principles to prevent glioma progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73999 | GEO | 2019/12/02

REPOSITORIES: GEO

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Project description:DNA methylation profiling of 26 individual isomorphic diffuse gliomas using Illumina HumanMethylation450 BeadChips or Illumina Infinium HumanMethylation850 BeadChips. Abstract: The “isomorphic subtype of diffuse astrocytoma” was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proliferation was low. All 24 cases sequenced were IDH-wildtype. In cluster analyses of DNA-methylation data, isomorphic diffuse gliomas formed a group clearly distinct from other glial/glio-neuronal brain tumours and normal hemispheric tissue, most closely related to paediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%). Gene fusions of MYBL1 or MYB with various gene partners were identified in 11/22 (50%) and were associated with an increased RNA-expression of the respective MYB-family gene. Integrating copy number alterations and available RNA sequencing data, 20/26 (77%) of isomorphic diffuse gliomas demonstrated MYBL1 (54%) or MYB (23%) alterations. Clinically, 89% of patients were seizure-free after surgery and all had a good outcome. In summary, we here define a distinct benign tumour class belonging to the family of MYB/MYBL1-altered gliomas. Isomorphic diffuse glioma occurs both in children and adults, has a concise morphology, frequent MYBL1- and MYB-alterations and a specific DNA-methylation profile. As an exclusively histological diagnosis may be very challenging and as paediatric MYB/MYBL1-altered diffuse astrocytomas may have the same gene fusions, we consider DNA-methylation profiling very helpful for their identification.

Project description:Diffuse infiltrating gliomas are the most common primary brain malignancy found in adults, and Glioblastoma multiforme, the highest grade glioma, is associated with a median survival of 7 months. Transcriptional profiling has been applied to 85 gliomas from 74 patients to elucidate glioma biology, prognosticate survival, and define tumor sub-classes. These studies reveal that transcriptional profiling of gliomas is more accurate at predicting survival than traditional pathologic grading, and that gliomas characteristically express coordinately regulated genes of one of four molecular signatures: neurogenesis, synaptic transmission, mitotic, or extra-cellular matrix. Elucidation of these survival associated molecular signatures will aid in tumor prognostication and define targets for future directed therapy. Evaluate a large number of diffuse infiltrating gliomas through transcriptional profiling. Glioma tumor sub-classes may be identified through large scale gene expression studies. All patients undergoing surgical treatment at the University of California, Los Angeles for primary brain cancers between 1996 and 2003 were invited to participate in this Institutional Review Board approved study. 74 of the patients participating in this broad protocol were analyzed as part of this study if their initial tumor was diagnosed as a grade III (n=24) or IV (n=50) glioma of any histologic type on initial surgical treatment and fresh frozen material was obtained. Only grade III and IV gliomas were included in this study as the distinction between these grades is subtle and prone to misclassification. The time in days elapsed from resection to the day of death, or if the patient has remained alive, to the current day was recorded for all samples studied. Patient ages at diagnosis varied from 18 to 82 years. There were 46 females and 28 males. Probes were prepared using standard Affymetrix protocols, and hybridized to Affymetrix HG-U133A and HG-U133B arrays.

Project description:Background: Signaling by receptor tyrosine kinases (RTK) is frequently dysregulated in gliomas. Inter-individual variability in the causes for dysregulated RTK signaling may have hampered the efficacy of targeted therapies. Using gene expression modules around key regulators in the RAS-RAF-MEK-MAPK cascade and in the phosphatidylinositol 3-kinase-AKT pathways, we developed a âRMPAâ clustering scheme to distinguish gliomas with varying extents of RTK signaling. Results: We identified gene modules consistently co-expressed with NF1 (NF1-M), Sprouty (SPRY-M) and PTEN (PTEN-M) in gliomas. Their signatures enabled robust clustering of adult diffuse gliomas of WHO grades II-IV into RMPAhigh and RMPAlow phenotypes in a morphology-independent manner. In five independent data sets from three continents containing more than 1500 adult diffuse gliomas, RMPAhigh gliomas were associated with poor prognosis while RMPAlow gliomas were not. The RMPAhigh and RMPAlow glioma subtypes showed distinct levels of the activities of RAS-RAF-MEK-MAPK cascade and PI3K-AKT pathway and harbored unique sets of genomic alterations in the RTK signaling-related genes. The RMPAhigh gliomas contained large numbers of immature vessel cells and tumor associated macrophages and both cell types expressed high levels of pro-angiogenic RTKs including MET, VEGFR1, KDR, EPHB4 and NRP1. Conclusion: Inter-glioma variability in RTK signaling activities can be defined using the RMPA clustering scheme. The combined signatures of NF1-M, SPRY-M and PTEN-M reflect RTK signaling activity both in the glioma cells and in the glioma microenvironment. Our data show that RTK signaling in the glioma microenvironment may play a pivotal role in glioma progression. Transcriptome data from 22 fresh gliomas (2 astrocytoma II, 1 oligodendrocytoma II, 7 oligoastrocytoma II, 4 anaplastic oligoastrocytoma III and 8 GBM) were obtained using Affymetrix Human Gene 1.0 ST Array. Unsupervised hierarchical clustering of the expression data for the SPRY-M, NF1-M and PTEN-M was performed on these transcriptome data to identify samples with RMPAhigh or RMPAlow signature.

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P120-catenin dependent glioma-cell networks drive growth and diffuse brain infiltration

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