Fibronectin expression in glioblastomas promotes cell cohesion, collective invasion of basement membrane in vitro and orthotopic tumor growth in mice

Serres, Émilie; Debarbieux, Franck; Stanchi, Fabio; Maggiorella, Laurence; Grall, Dominique; Turchi, Laurent; Burel‐Vandenbos, Fanny; Figarella‐Branger, Dominique; Virolle, Thierry; Rougon, Geneviève; Obberghen-Schilling, Ellen Van

doi:10.1038/onc.2013.305

Cited by 138 publications

(118 citation statements)

References 42 publications

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“…3, 2018; using in vivo models and patient samples [20,33,63,[70][71][72]. Differential gene expression analysis also demonstrated upregulation of several genes previously linked to GBM malignancy, such as the matrix metalloproteinases, PDGFB and PDGF receptors, TNC, FN1, and EGFR, consistent with previous findings using conventional cell culture and analysis of patient and xenograft-derived tumor specimens [54,61,[73][74][75]. KEGG pathway analysis additionally confirmed the over-representation of various signaling cascades commonly dysregulated in GBM amongst upregulated genes, such as Notch, NF-κβ, Jak-STAT, HIF-1, MAPK, Ras, and PI3K-Akt [9] [76] [77] [78], all in the case of GBM cells exposed to a perivascular environment.…”

Section: Gbm Progression Is Believed To Be Linked To the Interactionssupporting

confidence: 77%

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Harley

Ngo

2018

Preprint

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Glioblastoma (GBM) is the most common primary malignant brain tumor, with patients exhibiting poor survival (median survival time: 15 months). Difficulties in treating GBM include not only the inability to resect the diffusively-invading tumor cells but also therapeutic resistance. The perivascular niche within the GBM tumor microenvironment contributes significantly to tumor cell invasion, cancer stem cell maintenance, and has been shown to protect tumor cells from radiation and chemotherapy. In this study, we describe the development of an in vitro artificial perivascular niche (PVN), culturing endothelial and stromal cells along with GBM cells within a methacrylamide-functionalized gelatin hydrogel, in order to examine howthe presence of the PVN alters global genomic expression profiles. Using RNA-seq, we demonstrate that the inclusion of perivascular niche cells with GBM cells upregulates genes related to angiogenesis and remodeling, while downregulated genes are related to cell cycle and DNA damage repair.Signaling pathways and genes commonly implicated in GBM malignancy, such as MGMT, EGFR, PI3K-Akt signaling, and Ras/MAPK signaling are also upregulated in the presence of perivascular niche cells. We describe the kinetics of gene expression within the PVN hydrogels over a course of 14 days, observing the patterns associated with previously-observed GBMmediated endothelial network co-option and regression that are altered in the presence of covalently-bound hyaluronic acid. We finally examine the effect of PVN culture on GBM cell responsiveness to temozolomide, a frontline chemotherapy used clinically against GBM.Notably, the presence of a PVN leads to significantly increased TMZ resistance compared to hydrogels containing only GBM cells. Overall, these results demonstrate that inclusion of cellular and matrix-associated elements of the PVN within in vitro models of GBM provide critical signals to regulate the phenotype and therapeutic responsiveness of GBM cells.

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Section: Gbm Progression Is Believed To Be Linked To the Interactionssupporting

confidence: 77%

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Harley

Ngo

2018

Preprint

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“…However, recent in vivo studies suggest that in addition to paracrine functions (Yoshino et al, 2014), Fn1 could also signal in a cell-autonomous manner (Cseh et al, 2010;Liu et al, 2010;Serres et al, 2014;Stenzel et al, 2011). By using genetic and cell biological approaches, the studies reported in this paper are the first to demonstrate the requisite, cell-autonomous role of Fn1 in the regulation of cardiovascular development.…”

Section: Role Of Fn1 and Integrin α5 In Nc Development And Cardiovascmentioning

confidence: 73%

Neural crest cell-autonomous roles of fibronectin in cardiovascular development

Wang

Astrof

2015

Development

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The chemical and mechanical properties of extracellular matrices (ECMs) modulate diverse aspects of cellular fates; however, how regional heterogeneity in ECM composition regulates developmental programs is not well understood. We discovered that fibronectin 1 (Fn1) is expressed in strikingly non-uniform patterns during mouse development, suggesting that regionalized synthesis of the ECM plays cell-specific regulatory roles during embryogenesis. To test this hypothesis, we ablated Fn1 in the neural crest (NC), a population of multi-potent progenitors expressing high levels of Fn1. We found that Fn1 synthesized by the NC mediated morphogenesis of the aortic arch artery and differentiation of NC cells into vascular smooth muscle cells (VSMCs) by regulating Notch signaling. We show that NC Fn1 signals in an NC cell-autonomous manner through integrin α5β1 expressed by the NC, leading to activation of Notch and differentiation of VSMCs. Our data demonstrate an essential role of the localized synthesis of Fn1 in cardiovascular development and spatial regulation of Notch signaling.

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“…Indeed, it has already been shown that fibronectin and laminin increase migration and growth of GBM. 35,36 …”

Section: Resultsmentioning

confidence: 99%

Glioblastoma cells inhibit astrocytic p53-expression favoring cancer malignancy

et al. 2014

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The tumor microenvironment has a dynamic and usually cancer-promoting function during all tumorigenic steps. Glioblastoma (GBM) is a fatal tumor of the central nervous system, in which a substantial number of non-tumoral infiltrated cells can be found. Astrocytes neighboring these tumor cells have a particular reactive phenotype and can enhance GBM malignancy by inducing aberrant cell proliferation and invasion. The tumor suppressor p53 has a potential non-cell autonomous function by modulating the expression of secreted proteins that influence neighbor cells. In this work, we investigated the role of p53 on the crosstalk between GBM cells and astrocytes. We show that extracellular matrix (ECM) from p53+/− astrocytes is richer in laminin and fibronectin, compared with ECM from p53+/+ astrocytes. In addition, ECM from p53+/− astrocytes increases the survival and the expression of mesenchymal markers in GBM cells, which suggests haploinsufficient phenotype of the p53+/– microenvironment. Importantly, conditioned medium from GBM cells blocks the expression of p53 in p53+/+ astrocytes, even when DNA was damaged. These results suggest that GBM cells create a dysfunctional microenvironment based on the impairment of p53 expression that in turns exacerbates tumor endurance.

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Fibronectin expression in glioblastomas promotes cell cohesion, collective invasion of basement membrane in vitro and orthotopic tumor growth in mice

Cited by 138 publications

References 42 publications

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Neural crest cell-autonomous roles of fibronectin in cardiovascular development

Glioblastoma cells inhibit astrocytic p53-expression favoring cancer malignancy

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