Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells

Binda, Elena; Visioli, Alberto; Giani, Fabrizio; Trivieri, Nadia; Palumbo, Orazio; Restelli, Silvia; Dezi, Fabio; Mazza, Tommaso; Fusilli, Caterina; Legnani, Federico; Carella, Massimo; Meco, Francesco Di; Duggal, Rohit; Vescovi, Angelo L.

doi:10.1158/0008-5472.can-16-1693

Cited by 81 publications

(110 citation statements)

References 49 publications

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“…In this study, we used GSC cultures that were previously extensively characterized for their stem-like capacity (22,48). A recent publication proposed a critical role of the apelin/APLNR signaling pathway in GSC maintenance (49).…”

Section: Discussionmentioning

confidence: 99%

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Targeting APLN/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA/VEGFR2 Blockade in Glioblastoma

Mastrella

Hou

et al. 2019

Cancer Research

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Antiangiogenic therapy of glioblastoma (GBM) with bevacizumab, a VEGFA-blocking antibody, may accelerate tumor cell invasion and induce alternative angiogenic pathways. Here we investigate the roles of the proangiogenic apelin receptor APLNR and its cognate ligand apelin in VEGFA/VEGFR2 antiangiogenic therapy against distinct subtypes of GBM. In proneural GBM, apelin levels were downregulated by VEGFA or VEGFR2 blockade. A central role for apelin/APLNR in controlling GBM vascularization was corroborated in a serial implantation model of the angiogenic switch that occurs in human GBM. Apelin and APLNR are broadly expressed in human GBM, and knockdown or knockout of APLN in orthotopic models of proneural or classical GBM subtypes significantly reduced GBM vascularization compared with controls. However, reduction in apelin expression led to accelerated GBM cell invasion. Analysis of stereotactic GBM biopsies from patients as well as from in vitro and in vivo experiments revealed increased dissemination of APLNR-positive tumor cells when apelin levels were reduced. Application of apelin-F13A, a mutant APLNR ligand, blocked tumor angiogenesis and GBM cell invasion. Furthermore, cotargeting VEGFR2 and APLNR synergistically improved survival of mice bearing proneural GBM. In summary, we show that apelin/APLNR signaling controls GBM angiogenesis and invasion and that both pathologic features are blunted by apelin-F13A. We suggest that apelin-F13A can improve the efficiency and reduce the side effects of established antiangiogenic treatments for distinct GBM subtypes.Significance: Pharmacologic targeting of the APLNR acts synergistically with established antiangiogenic treatments in glioblastoma and blunts therapy resistance to current strategies for antiangiogenesis.

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Section: Discussionmentioning

confidence: 99%

“…Cell culture GBM stem-like cell (GSC) were derived from human glioblastoma biopsies [as previously reported for NCH644 and NCH588J (20); GBM10, GBM13 and GBM14 (21); and GBM5av to 10av (22)] and were maintained under stem cell cultivation conditions in DMEM-F12 (catalog no. 11320-074) supple-mented with 1 Â B27 (catalog no.…”

Section: Methodsmentioning

confidence: 99%

Targeting APLN/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA/VEGFR2 Blockade in Glioblastoma

Mastrella

Hou

et al. 2019

Cancer Research

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“…GBM is characterized by complex tissue heterogeneity, in which there is a class of stem cell-like tumor-initiating cells, called GSCs, which have the ability to self-renew, grow continuously and differentiate into multiple neural cell types [34][35][36]. Further studies found that GSCs are key factors leading to the occurrence, recurrence, treatment tolerance and poor prognosis of glioma [35,[37][38][39][40]. We successfully propagated eight human GSC lines with four different molecular subtypes and found the highest PSAP expression and secretion in mesenchymal GSCs, as determined by western blotting and ELISA.…”

Section: Discussionmentioning

confidence: 99%

Prosaposin is a biomarker of mesenchymal glioblastoma and regulates mesenchymal transition through the TGF‐β1/Smad signaling pathway

Jiang

Zhou

Hou

et al. 2019

The Journal of Pathology

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Mesenchymal glioblastoma (GBM) is the most aggressive subtype of GBM. Our previous study found that neurotrophic factor prosaposin (PSAP) is highly expressed and secreted in glioma and can promote the growth of glioma. The role of PSAP in mesenchymal GBM is still unclear. In this study, bioinformatic analysis, western blotting and RT‐qPCR were used to detect the expression of PSAP in different GBM subtypes. Human glioma cell lines and patient‐derived glioma stem cells were studied in vitro and in vivo, revealing that mesenchymal GBM expressed and secreted the highest level of PSAP among four subtypes of GBM, and PSAP could promote GBM invasion and epithelial–mesenchymal transition (EMT)‐like processes in vivo and in vitro. Bioinformatic analysis and western blotting showed that PSAP mainly played a regulatory role in GBM invasion and EMT‐like processes via the TGF‐β1/Smad signaling pathway. In conclusion, the overexpression and secretion of PSAP may be an important factor causing the high invasiveness of mesenchymal GBM. PSAP is therefore a potential target for the treatment of mesenchymal GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

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“…This study explores TSPO and LAT1 expression in human and murine GBM tissue from different GBM subtypes (Table A1). GBM stem-like cells (GSCs) were derived from human GBM of different genetic subtypes, namely proneural [20,21] and classical [22], and were cultured as spheroids until xenografting them into immunodeficient mouse brains to produce GBM. Mouse transgenic GSCs used to model genetic GBM subtypes were derived from transgenic neural precursor cells that were additionally transduced to carry typical driver mutations for proneural (p53 KO PDGFB) or classical (cdkn2a KO EGFRvIII) GBM subtypes [23,24] and were kept under stem cell-like conditions until orthotopic implantation into immunocompetent mice.…”

Section: Introductionmentioning

confidence: 99%

Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells

Cai

Kirchleitner

Zhao

et al. 2020

IJMS

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Molecular imaging is essential for diagnosis and treatment planning for glioblastoma patients. Positron emission tomography (PET) with tracers for the detection of the solute carrier family 7 member 5 (SLC7A5; also known as the amino acid transporter light chain L system, LAT1) and for the mitochondrial translocator protein (TSPO) is successfully used to provide additional information on tumor volume and prognosis. The current approaches for TSPO-PET and the visualization of tracer ([18F] Fluoroethyltyrosine, FET) uptake by LAT1 (FET-PET) do not yet exploit the full diagnostic potential of these molecular imaging techniques. Therefore, we investigated the expression of TSPO and LAT1 in patient glioblastoma (GBM) samples, as well as in various GBM mouse models representing patient GBMs of different genetic subtypes. By immunohistochemistry, we found that TSPO and LAT1 are upregulated in human GBM samples compared to normal brain tissue. Next, we orthotopically implanted patient-derived GBM cells, as well as genetically engineered murine GBM cells, representing different genetic subtypes of the disease. To determine TSPO and LAT1 expression, we performed immunofluorescence staining. We found that both TSPO and LAT1 expression was increased in tumor regions of the implanted human or murine GBM cells when compared to the neighboring mouse brain tissue. While LAT1 was largely restricted to tumor cells, we found that TSPO was also expressed by microglia, tumor-associated macrophages, endothelial cells, and pericytes. The Cancer Genome Atlas (TCGA)-data analysis corroborates the upregulation of TSPO in a bigger cohort of GBM patient samples compared to tumor-free brain tissue. In addition, AIF1 (the gene encoding for the myeloid cell marker Iba1) was also upregulated in GBM compared to the control. Interestingly, TSPO, as well as AIF1, showed significantly different expression levels depending on the GBM genetic subtype, with the highest expression being exhibited in the mesenchymal subtype. High TSPO and AIF1 expression also correlated with a significant decrease in patient survival compared to low expression. In line with this finding, the expression levels for TSPO and AIF1 were also significantly higher in (isocitrate-dehydrogenase wild-type) IDHWT compared to IDH mutant (IDHMUT) GBM. LAT1 expression, on the other hand, was not different among the individual GBM subtypes. Therefore, we could conclude that FET- and TSPO-PET confer different information on pathological features based on different genetic GBM subtypes and may thus help in planning individualized strategies for brain tumor therapy in the future. A combination of TSPO-PET and FET-PET could be a promising way to visualize tumor-associated myeloid cells and select patients for treatment strategies targeting the myeloid compartment.

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Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells

Cited by 81 publications

References 49 publications

Targeting APLN/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA/VEGFR2 Blockade in Glioblastoma

Targeting APLN/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA/VEGFR2 Blockade in Glioblastoma

Prosaposin is a biomarker of mesenchymal glioblastoma and regulates mesenchymal transition through the TGF‐β1/Smad signaling pathway

Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells

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