glioblastoma   58

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A Novel Small-Molecule Inhibitor of MRCK Prevents Radiation-Driven Invasion in Glioblastoma | Cancer Research
radiation increases MRCK (which is up at the edges of invasive tumors also) and cdc42 to mrck may lead to mesenchymal invasion

Glioblastoma (GBM) is an aggressive and incurable primary brain tumor that causes severe neurologic, cognitive, and psychologic symptoms. Symptoms are caused and exacerbated by the infiltrative properties of GBM cells, which enable them to pervade the healthy brain and disrupt normal function. Recent research has indicated that although radiotherapy (RT) remains the most effective component of multimodality therapy for patients with GBM, it can provoke a more infiltrative phenotype in GBM cells that survive treatment. Here, we demonstrate an essential role of the actin-myosin regulatory kinase myotonic dystrophy kinase-related CDC42-binding kinase (MRCK) in mediating the proinvasive effects of radiation. MRCK-mediated invasion occurred via downstream signaling to effector molecules MYPT1 and MLC2. MRCK was activated by clinically relevant doses per fraction of radiation, and this activation was concomitant with an increase in GBM cell motility and invasion. Furthermore, ablation of MRCK activity either by RNAi or by inhibition with the novel small-molecule inhibitor BDP-9066 prevented radiation-driven increases in motility both in vitro and in a clinically relevant orthotopic xenograft model of GBM. Crucially, treatment with BDP-9066 in combination with RT significantly increased survival in this model and markedly reduced infiltration of the contralateral cerebral hemisphere.
mrck  Glioblastoma  invasion  mesenchymal_motion  radiation  cdc42 
5 weeks ago by Segalllab
DSE promotes aggressive glioma cell phenotypes by enhancing HB-EGF/ErbB signaling
Synergy of GAG proteoglycans with HB-EGF in glioblastoma. Though their EGF and NRG1 peptides did not have heparin binding domains so I suspect NRG1 signaling is also increased.


"Remodeling of the extracellular matrix (ECM) in the tumor microenvironment promotes glioma progression. Chondroitin sulfate (CS) proteoglycans appear in the ECM and on the cell surface, and can be catalyzed by dermatan sulfate epimerase to form chondroitin sulfate/dermatan sulfate (CS/DS) hybrid chains. Dermatan sulfate epimerase 1 (DSE) is overexpressed in many types of cancer, and CS/DS chains mediate several growth factor signals. However, the role of DSE in gliomas has never been explored. In the present study, we determined the expression of DSE in gliomas by consulting a public database and conducting immunohistochemistry on a tissue array. Our investigation revealed that DSE was upregulated in gliomas compared with normal brain tissue. Furthermore, high DSE expression was associated with advanced tumor grade and poor survival. We found high DSE expression in several glioblastoma cell lines, and DSE expression directly mediated DS chain formation in glioblastoma cells. Knockdown of DSE suppressed the proliferation, migration, and invasion of glioblastoma cells. In contrast, overexpression of DSE in GL261 cells enhanced these malignant phenotypes and in vivo tumor growth. Interestingly, we found that DSE selectively regulated heparin-binding EGF-like growth factor (HB-EGF)-induced signaling in glioblastoma cells. Inhibiting epidermal growth factor receptor (EGFR) and ErbB2 with afatinib suppressed DSE-enhanced malignant phenotypes, establishing the critical role of the ErbB pathway in regulating the effects of DSE expression. This evidence indicates that upregulation of DSE in gliomas contributes to malignant behavior in cancer cells. We provide novel insight into the significance of DS chains in ErbB signaling and glioma pathogenesis.
heparan_sulfate  chondroitin_sulfate  HB-EGF  Glioblastoma  GL261 
9 weeks ago by Segalllab
In Search for Reliable Markers of Glioma-Induced Polarization of Microglia
Expression analysis of immortalized (?) microglial lines cocultured with U87 or LN18 - need to ch



"Immune cells accumulating in the microenvironment of malignant tumors are tumor educated and contribute to its growth, progression, and evasion of antitumor immune responses. Glioblastoma (GBM), the common and most malignant primary brain tumor in adults, shows considerable accumulation of resident microglia and peripheral macrophages, and their polarization into tumor-supporting cells. There are controversies regarding a functional phenotype of glioma-associated microglia/macrophages (GAMs) due to a lack of consistent markers. Previous categorization of GAM polarization toward the M2 phenotype has been found inaccurate because of oversimplification of highly complex and heterogeneous responses. In this study, we characterized functional responses and gene expression in mouse and human microglial cultures exposed to fresh conditioned media [glioma-conditioned medium (GCM)] from human U87 and LN18 glioma cells. Functional analyses revealed mutual communication reflected by strong stimulation of glioma invasion by microglial cells and increased microglial phagocytosis after GCM treatment. To define transcriptomic markers of GCM-activated microglia, we performed selected and global gene expression analyses of stimulated microglial cells. We found activated pathways associated with immune evasion and TGF signaling. We performed computational comparison of the expression patterns of GAMs from human GBMs and rodent experimental gliomas to select genes consistently changed in different datasets. The analyses of marker genes in GAMs from different experimental models and clinical samples revealed only a small set of common genes, which reflects variegated responses in clinical and experimental settings. Tgm2 and Gpnmb were the only two genes common in the analyzed data sets. We discuss potential sources of the observed differences and stress a great need for definitive elucidation of a functional state of GAMs.
microglia  Glioblastoma  coculture  U87  ln18  gene_expression  macrophage_polarization  polarization 
november 2018 by Segalllab
Decrease of VEGF-A in myeloid cells attenuates glioma progression and prolongs survival in an experimental glioma model
Have one image of GL261 in VEGF KO brain showing increased invasion - possibly due to more hypoxia (not what they think of)? They focus on reduced TGFB production by the microglia.

"
Background

Glioblastomas are highly vascularized tumors with a prominent infiltration of macrophages/microglia whose role in promoting glioma growth, invasion, and angiogenesis has not been fully elucidated.
Methods

The contribution of myeloid-derived vascular endothelial growth factor (VEGF) to glioma growth was analyzed in vivo in a syngeneic intracranial GL261 glioma model using a Cre/loxP system to knock out the expression of VEGF-A in CD11b + myeloid cells. Changes in angiogenesis-related gene expression profile were analyzed in mutant bone marrow-derived (BMD) macrophages in vitro. Furthermore, we studied the influence of macrophages on GL261 growth, invasiveness, and protein expression profile of angiogenic molecules as well as the paracrine effect of mutant macrophages on angiogenesis in vitro.
Results

Myeloid cell-restricted VEGF-A deficiency leads to a growth delay of intracranial tumors and prolonged survival. The tumor vasculature in mutant mice was more regular, with increased pericyte coverage. Expression analysis revealed significant downregulation of VEGF-A and slight upregulation of TGFβ-1 in BMD macrophages from mutant mice. Endothelial tube formation was significantly decreased by conditioned media from mutant macrophages. The expression of angiogenesis-related proteins in GL261 glioma cells in co-culture experiments either with wild-type or mutant macrophages remained unchanged, indicating that effects observed in vivo are due to myeloid-derived VEGF-A deficiency.
Conclusions

Our results highlight the importance of VEGF derived from tumor-infiltrating myeloid cells for initiating vascularization in gliomas. The combination of antiangiogenic agents with myeloid cell-targeting strategies might provide a new therapeutic approach for glioblastoma patients
VEGF  myeloid_KO  microglia  GL261  Glioblastoma  TGFB 
november 2018 by Segalllab
Harmful networks in the brain and beyond | Science
TNTs and focus on glioma

Communication in networks is the basis of many social and biological functions. Recent findings have added an uncomfortable twist to this view: Tumors can function as communicating networks, too. In several malignancies such as incurable brain tumors, long protrusions extend from cancer cells, connecting them to a functional syncytium and colonizing normal tissue. These invasive and network-building membrane tubes raise interesting questions about cancer biology.
TNTs  Glioblastoma 
april 2018 by Segalllab
Single-Cell RNA-Seq Analysis of Infiltrating Neoplastic Cells at the Migrating Front of Human Glioblastoma: Cell Reports
Title says it all - Glioblastoma (GBM) is the most common primary brain cancer in adults and is notoriously difficult to treat because of its diffuse nature. We performed single-cell RNA sequencing (RNA-seq) on 3,589 cells in a cohort of four patients. We obtained cells from the tumor core as well as surrounding peripheral tissue. Our analysis revealed cellular variation in the tumor’s genome and transcriptome. We were also able to identify infiltrating neoplastic cells in regions peripheral to the core lesions. Despite the existence of significant heterogeneity among neoplastic cells, we found that infiltrating GBM cells share a consistent gene signature between patients, suggesting a common mechanism of infiltration. Additionally, in investigating the immunological response to the tumors, we found transcriptionally distinct myeloid cell populations residing in the tumor core and the surrounding peritumoral space. Our data provide a detailed dissection of GBM cell types, revealing an abundance of information about tumor formation and migration.
Glioblastoma  single_cell_rnaseq 
march 2018 by Segalllab
Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas | Oncogene
Using the PDGF model - see effects on tumor growth...



"We found that PLX3397, an inhibitor of colony stimulating factor-1 receptor (CSF-1R), blocks glioma progression, markedly suppresses tumor cell proliferation and reduces tumor grade. By contrast, the multi-targeted tyrosine kinase inhibitors dovitinib and vatalanib, which directly target tumor cells, exert minimal anti-tumoral effects in vivo, despite killing glioma cells in vitro, suggesting a TME-mediated resistance mechanism may be involved. Interestingly, PLX3397 interferes with tumor-mediated education of macrophages and consequently restores the sensitivity of glioma cells to tyrosine kinase inhibitors in vivo in preclinical combination trials. Our findings thus demonstrate that microenvironmental alteration by CSF-1R blockade renders tumor cells more susceptible to receptor tyrosine kinase inhibition in a preclinical glioblastoma model, which may have important translational relevance."
plx3397  TAM  Glioblastoma  macrophage_polarization  drug_resistance 
march 2018 by Segalllab
Tumor Purity as an Underlying Key Factor in Glioma | Clinical Cancer Research
analysis of purity of cell types - highly pure gliomas are less aggressive and better prognosis than those that attract alot of stromal/macrophages.
Glioblastoma  Macrophage  Prognosis 
february 2018 by Segalllab
Twitter
Smart bomb oncolytic virus stirs immune response vs. recurrent . 20 percent response rate with OS beyo…
Glioblastoma  from twitter_favs
february 2018 by maverickny
Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment | Genome Biology | Full Text
Do RNAseq without flow. find blood derived and microglia derived TAMs, with microglial near invasive border and blood derived in vascular and necrotic areas. Also see that the TAM can express a mix of M1 and M2 markers (including TNFA as M1 marker), and changes in TAM distribution between LGG and GBM. Suggest P2RY12 as microglia specific marker.

"Our primary finding is that while blood-derived TAMs do significantly infiltrate pre-treatment human gliomas, they do not adopt the phenotype or regional distribution of microglial TAMs. Compared to microglia, blood-derived TAMs upregulate immunosuppressive cytokines, markers of active phagocytosis, and markers of an activated TCA cycle. To derive this result, we performed scRNA-seq of clinical glioma specimen. This uniquely enabled us to quantify differences between subpopulations of TAMs, in vivo. Our scRNA-seq identified a novel gene signature that distinguishes blood-derived macrophages from microglia in both malignant and non-malignant conditions. We mapped this signature to RNA-seq of microdissections from defined glioma anatomical structures. From that mapping, we show that microglia are enriched in the leading edge of tumor infiltration, while blood-derived TAMs are enriched near blood vessels and necrotic foci. The gene signature of blood-derived TAMs significantly and negatively correlates with survival in LGG, but the microglial-TAM signature does not. Collectively, these results support the idea that there are durable gene markers of macrophage lineage and that macrophage ontogeny is critical to shaping macrophage activation in the glioma microenvironment.

CX3CR1 is frequently used to identify microglia in tumor specimen [24]. However, we and others have found that purinergic receptors (e.g. P2RY12) are more specific than CX3CR1, as markers of microglial TAMs [9, 16, 17]. We present here a comprehensive list of markers to isolate TAMs by ontogeny, from human and mouse gliomas."
microglia  TAMs  Glioblastoma  tnfa  scRNAseq  P2RY12 
january 2018 by Segalllab
andrto — Glioblastoma, brain tumour that took Gord Downie's...
Glioblastoma, brain tumour that took Gord Downie's life, tough to treat: doctors | Glioblastoma
Glioblastoma  from twitter
october 2017 by heyyouapp
Malignant Astrocytic Tumor Progression Potentiated by JAK-mediated Recruitment of Myeloid Cells | Clinical Cancer Research
demonstration of increased circulating mdscs with higher grade glioma - JAK inhibition may help by reducing their production in the bone marrow and slowing progression
JAK/STAT  MDSC  Glioblastoma  bone_marrow  TAMs 
october 2017 by Segalllab
Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy : Nature : Nature Research
More evidence that chemotherapy initially works for glioblastoma -- but it selects for the stem cells that are resistant to it, which eventually create form tumor growth that is resistant to the chemo. > We also identify rare ‘outlier’ clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant glioblastoma stem cells
glioblastoma  cancer  chemotherapy 
september 2017 by porejide
Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells | Cancer Research
wnt5a can stimulate glioma invasion - is up in the cocultures - possible mechanism of microglia stimulated invasion?
glioblastoma  invasion  wnt5a  microglia  coculture 
may 2017 by Segalllab
Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies: Cell Reports
Very elegant dissection of microglial vs bone marrow macrophage contributions to GL261 and tva tumors and avoiding the irradiation issues. Show AREG upregulation in TAMS. Has microarray and ATAC data.
glioblastoma  microglia  macrophage  TAM  areg  microarray  tva_induced_gliomas 
april 2017 by Segalllab
Twitter
Investigadores de y de descubren cómo combatir Dr.Fernández Luna,Dra.Terán…
Glioblastoma  from twitter_favs
october 2016 by tguemes

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