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Cell-specific crosstalk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone

ABSTRACT: Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially due to subventricular zone (SVZ) contact. Despite this, crosstalk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. Additionally, GBM brain tumor initiating cells (BTICs) increase expression of CTSB upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Finally, we show LV-proximal CTSB upregulation in patients, showing the relevance of this crosstalk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243836 | GEO | 2024/06/23

REPOSITORIES: GEO

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Cell-specific crosstalk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone

Project description:Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially due to subventricular zone (SVZ) contact. Despite this, crosstalk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. Additionally, interaction with NPCs increases cathepsin B (CTSB) expression in GBM brain tumor initiating cells (BTICs). Lentiviral knockdown and recombinant protein experiments reveal both cell-intrinsic and soluble CTSB promote malignancy-associated BTIC phenotypes. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Finally, we show LV-proximal CTSB upregulation in patients, showing the relevance of this crosstalk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.

2024-06-24 | PXD044773 | Pride

Comprehensive genomic profiling of matched glioblastoma tumors, cell-lines and xenografts reveals genomic stability and adaptation to disparate growth environments

Project description:Glioblastoma Multiforme (GBM) is the most deadly brain tumor, and currently lacks effective treatment options. Brain tumor initiating cells (BTICs) and orthotopic xenografts are widely used in investigating GBM biology and new therapies for this aggressive disease. However, the genomic characteristics and molecular resemblance of these models to GBM tumors remain undetermined. We used massively parallel sequencing technology to decode the genomes and transcriptomes of BTICs and xenografts and their matched tumors in order to delineate the potential impacts of the distinct growth environments. Using data generated from whole‐genome sequencing of 201 samples and RNA sequencing of 118 samples, we showed that typical GBM genomic driver alterations found in the tumors were retained in BTICs and xenografts. In contrast, gene expression and methylation profiles indicated higher levels of divergence, likely due to the different growth environment for each sample type. These findings suggest that a comprehensive genomic understanding of in vitro and in vivo GBM model systems is crucial for interpreting data from drug‐screens, and can help control for biases introduced by cell culture conditions and the microenvironment in mouse models.

2019-03-22 | GSE128654 | GEO

Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy

Project description:Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM is limited to the resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrated clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Edge cells show a higher capacity for infiltrative growth, while core cells demonstrate greater therapy resistance. Investigation of intercellular signaling between these two cell populations uncovered the paracrine crosstalk from tumor core that provokes malignancy and therapy resistance of edge cells. These phenotypic alterations were initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence.

2020-07-03 | GSE153746 | GEO

Brain tumor initiating cell response to microglia

Project description:Determination of the mechanism by which microglia regulate growth of brain tumor initiating cells (BTICs) and differentiation. Results identify the factors involved in the regulation and provide mechanistic basis. We subjected brain tumor initiating cells to microarray to determine the genes involved in BTICs growth and differentiation when exposed to microglia conditioned medium (MCM) for 6h. BTICs were grown in MCM or control medium for 6h, and media was removed and then the cells were subjected for RNA extraction and hybridization on Affymatrix microarrays. Three (3) control and four (4) MCM samples were generated. The overall objective was to collect the RNA from the MCM exposed differentiated BTICs.

2013-11-06 | E-GEOD-52127 | biostudies-arrayexpress

Nuclear transport surveillance of p53 by nuclear pores in glioblastoma

Project description:Nuclear pore complexes (NPCs) are the central apparatus of nucleocytoplasmic transport. Disease-specific alterations of NPCs contribute to the pathogenesis of many cancers; however, the roles of NPCs in glioblastoma (GBM) are unknown. In this study, we report genomic amplification of NUP107, a component of NPCs, in GBM and show that NUP107 is overexpressed simultaneously with MDM2, a critical E3 ligase that mediates p53 degradation. Depletion of NUP107 inhibits the growth of GBM cell lines through p53 protein stabilization. Mechanistically, NPCs establish a p53 degradation platform via an export pathway coupled with 26S proteasome tethering. NUP107 is the keystone for NPC assembly; the loss of NUP107 affects the integrity of the NPC structure, and thus the proportion of 26S proteasome in the vicinity of nuclear pores significantly decreases. Together, our findings establish roles of NPCs in transport surveillance and provide insights into p53 inactivation in GBM.

2023-08-19 | GSE216888 | GEO

Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of Glioblastoma

Project description:Dilsulfiram together with Copper shows efficacy against patient derived Brain Tumor Initiating Cells (BTICs) in vitro and sensitizes BTICs to the DNA damaging agent TMZ. In addition, preclinical assessment found that DSF/Cu potentiaties the efficicacy of TMZ in vivo and prolongs survival. We used microarrays to detail the global profile of gene expression underlying DSF/Cu treatment in vitro and in vivo in BTICs.

2016-03-21 | GSE76146 | GEO

Brain tumor initiating cell response to microglia

2013-11-06 | GSE52127 | GEO

Cellular Senescence in Progenitor Cells Contributes to Diminished Remyelination Potential in Progressive Multiple Sclerosis

Project description:Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a pro-inflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from primary progressive multiple sclerosis (PPMS) patient induced pluripotent stem (iPS) cell lines failed to promote oligodendrocyte progenitor cell (OPC) maturation whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2+ progenitor cells within white matter lesions of human progressive MS autopsy brain tissues and PPMS patient iPS-derived NPCs. Expression of cellular senescence genes in PPMS NPCs was found to be reversible by treatment with rapamycin which then enhanced PPMS NPC support for oligodendrocyte differentiation. A proteomic analysis of the PPMS NPC secretome identified high mobility group box-1 (HMGB1), which was found to be a senescence-associated inhibitor of oligodendrocyte differentiation. Transcriptome analysis of OPCs revealed that senescent NPCs induced expression of epigenetic regulators mediated by extracellular HMGB1. Lastly, we determined that progenitor cells are a source of elevated HMGB1 in human white matter lesions. Based on these data, we conclude that cellular senescence contributes to altered progenitor cell functions in demyelinated lesions in MS. Moreover, these data implicate cellular aging and senescence as a process that contributes to remyelination failure in progressive MS which may impact how this disease is modeled and inform development of future myelin regeneration strategies.

2019-11-12 | PXD013060 | Pride

Comprehensive genomic profiling of matched glioblastoma tumours, cell-lines, and xenografts reveals genomic stability and adaptation to disparate growth environments

Project description:The mandate of this project was to use drug screening to deliver new drugs for glioblastoma (GBM) to clinical trials, and perform genomic assessment of GBM to discover new therapeutic targets and predictors of response. The sequencing data in this set was derived from GBM patient tumor samples, matched brain tumor initiating cells lines (BTICs), and tumor tissue derived from orthotopic implants.

| EGAS00001002709 | EGA

Identification of tumor antigens among the HLA peptidomes of Glioblastoma tumors and plasma

Project description:Glioblastoma multiforme (GBM) is the most aggressive brain tumor with poor prognosis to most patients. Immunotherapy of GBM is a potentially beneficial treatment option, whose optimal implementation may depend on familiarity with tumor specific antigens, presented as HLA peptides by the GBM cells. Furthermore, early detection of GBM, such as by a routine blood test, may improve survival, even with the current treatment modalities. This study includes large-scale analyses of the HLA peptidome (immunopeptidome) of the plasma-soluble HLA molecules (sHLA) of 142 plasma samples and the membranal HLA of GBM tumors of 10 tumor samples of the same patients. Tumor samples were fresh-frozen immediately after surgery and plasma samples were collected before, and at multiple visits after surgery. In total, this HLA peptidome analysis involved 52 different HLA allotypes and resulted in the identification of more than 35,000 different HLA peptides. Strong correlations were observed in the signal intensities and in the repertoires of identified peptides between the tumors and plasma-soluble HLA peptidomes of the same patients; yet, low correlations were observed between these HLA peptidomes and the tumors’ proteomes. HLA peptides derived from Cancer/Testis Antigens (CTAs) were selected based on their presence among the HLA peptidomes of the patients and absence of expression of their source genes from any healthy and essential human tissues, except from immune-privileged sites. Additionally, peptides were selected as potential biomarkers if their levels in the plasma-sHLA peptidome were significantly reduced after the removal of tumor mass. The CTAs identified among the analyzed HLA peptidomes provide new opportunities for personalized immunotherapy and for early diagnosis of GBM.

2019-06-11 | PXD008127 | Pride

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