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Integrative and Quantitative Analysis of Tumor Progression Reveals Fundamental Properties of Glioblastoma

ABSTRACT: Principle of tumor growth is one fundamental aspect of cancer biology and it remains to be superficially understood. Here we developed a set of genetic and mathematic tools allow integrative analysis of mouse glioblastoma (GBM) progression. Quantitative temporal imaging of mouse GBM and mathematic modeling suggest that mouse GBM grows exponentially, which led to the discovery that a sustainable exponential growth requires outward migrating brain tumor stem cells (BTSCs). Quantitative single cell tracing of BTSCs in vivo unravels symmetric expansion of BTSCs, asymmetric differentiation, and a non-reversible differentiation process during tumor progression. Mosaic tracing of BTSCs and non-BTSCs reveals a cellular temporal dynamic changes and cellular turnover. These experimentally collected parameters were integrated step by step to a quantitative mathematic model of GBM growth, which faithfully predicts tumor cellular architecture, tumor response to chemotherapy and BTSC therapy. Bulk and single cell RNA-Seq reveals distinct molecular hierarchy and molecular heterogeneity in BTSCs, which was confirmed by analyzing human GBM single cell RNA-Seq results. This study reveals basic developmental principles that govern tumor development, which provides novel understanding of cancer development, tumor heterogeneity and new approaches to treat GBM.

ORGANISM(S): Mus musculus

PROVIDER: GSE114456 | GEO | 2024/05/01

REPOSITORIES: GEO

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Integrative and Quantitative Analysis of Tumor Progression Reveals Fundamental Properties of Glioblastoma

Project description:The principle of tumor growth is one of the most fundamental aspects in cancer biology and it remains to be superficially understood. Here we developed a set of genetic and mathematical tools for integrative analysis of mouse glioblastoma (GBM) progression. Quantitative temporal imaging of mouse GBM and mathematical modeling suggest that mouse GBM grows exponentially, which led to the discovery that a sustainable exponential growth requires outward migrating brain tumor stem cells (BTSCs). Quantitative single cell tracing of BTSCs in vivo unravels symmetric expansion of BTSCs, asymmetric differentiation, and a non-reversible differentiation process during tumor progression. Mosaic tracing of BTSCs and non-BTSCs reveals cellular dynamic changes and turnover. These experimentally collected parameters were integrated step by step to a quantitative mathematical model of GBM growth, which faithfully predicts tumor cellular architecture, tumor response to chemotherapy and BTSC therapy. Bulk and single cell RNA-Seq reveals distinct molecular hierarchy and molecular heterogeneity in BTSCs, which was confirmed by analyzing human GBM single-cell RNA-Seq results. This study reveals fundamental developmental principles that govern tumor growth, which provides insights into understanding cancer development, tumor heterogeneity and GBM therapy.

2022-02-02 | GSE126212 | GEO

Genome-wide analysis of GBM-derived brain tumor stem cells-like (BTSCs)

Project description:Genome-wide analysis of GBM-derived brain tumor stem cells-like (BTSCs) collected at the Freiburg Medical Center and UAB (JX6)

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Project description:Genome-wide analysis of GBM-derived brain tumor stem cells-like (BTSCs)

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Brain tumor stem cell dependence on glutaminase reveals a metabolic vulnerability through the amino acid deprivation response pathway

Project description:Cancer cells can metabolize glutamine to replenish TCA cycle intermediates, leading to a dependence on glutaminolysis for cell survival. However, a mechanistic understanding of the role that glutamine metabolism has on the survival of glioblastoma (GBM) brain tumor stem cells (BTSCs) has not yet been elucidated. Here we report that, across a panel of twenty glioblastoma BTSC lines, glutaminase (GLS) inhibition showed a variable response – from complete blockade of cell growth to absolute resistance. Surprisingly, BTSC sensitivity to GLS inhibition was a result of reduced intracellular glutamate triggering the amino acid deprivation response (AADR) and not due to the contribution of glutaminolysis to the TCA cycle. Moreover, BTSC sensitivity to GLS inhibition negatively correlated with the expression of the astrocytic glutamate transporters EAAT1 and EAAT2. Blocking glutamate transport in BTSCs with high EAAT1/EAAT2 expression rendered these cells susceptible to GLS inhibition, triggering the AADR, and limiting cell growth. These findings uncover a unique metabolic vulnerability in BTSCs, support the therapeutic targeting of the upstream activators and downstream effectors of the AADR pathway in GBM, and demonstrate that gene expression patterns reflecting the cellular hierarchy of the tissue of origin can alter the metabolic requirements of the cancer stem cell population.

2020-12-25 | GSE155300 | GEO

Effect on gene expression profilng of BTSCs following HDAC1/2 inhibition with romidepsin.

Project description:To investigate the roles of HDAC1/2 in regulating the transcriptional programs associated with BTSC stem cell, growth and differentiation features, we performed RNA-seq using samples obtained from romidepsin treated versus DMSO vehicle treated GBM BTSCs.

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RAPID RESISTANCE TO BET INHIBITORS IS MEDIATED BY FGFR1 IN GLIOBLASTOMA

Project description:Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that intrinsic resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Additionally, small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.

2023-10-23 | GSE245624 | GEO

Genome-wide analysis of the function of Tlx in regulating mouse brain glioma gene expression

Project description:Analysis of the function of Tlx in regulating brain tumor stem cells (BTSCs) at the gene expression level. Based on our knowledge, we know that Tlx is specifically expressed in the neural stem cells in mouse brain. It also functionally regulates neurogenesis during the postnatal stages. The hypothesis tested in the present study is that Tlx influences the maintenance and progression of mouse brain gliomas through regulating the self-renewal of BTSCs and it is also a specific marker of brain tumor stem cells (BTSCs). Results provide important information about the function of Tlx in brain gliomas.

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Involvement of miRNAs in the induced differentiation of glioblastoma multiforme brain tumor stem-like cells [Exiqon miRNA array]

Project description:Brain tumor neurospheres (BTCSs) are cancer cells with neural stem cell-like properties found in the fatal brain tumor glioblastoma multiforme (GBM). These cells account for less than 1% of total tumor cells, are poorly differentiated and are believed to be involved in tumor induction, progression, treatment resistance and relapse. Specific miRNAs play important roles in modulating the proliferation and differentiation of neural stem cells, therefore, we aimed to identify miRNAs controlling differentiation in GBM-BTSCs through high throughput screening miRNA array profiling. We compared the miRNA expression profiles at the neurosphere state and upon 4 and 14 days of differentiation by using LIMMA, finding 21 differentially expressed miRNAs : hsa-miR-103, hsa-miR-106a, hsa-miR-106b, hsa-miR-15b, hsa-miR-17, hsa-miR-19a, hsa-miR-20a, hsa-miR-25, hsa-miR-301a and hsa-miR-93 were found up-regulated upon differentiation, while hsa-miR-100, hsa-miR-1259, hsa-miR-21, hsa-miR-22, hsa-miR-221, hsa-miR-222, hsa-miR-23b, hsa-miR-27a, hsa-miR-27b, hsa-miR-29a and hsa-miR-29b were down-regulated. Expression of 11 of the 21 miRNAs was examined by qPCR and 7 of them were validated: hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222 increased their expression upon differentiation, while hsa-miR-93 and hsa-miR-106a were inhibited. Functional studies demonstrated that miR-21 over-expression induced the expression of glial and/or neuronal cell markers in the neurospheres, possibly due to SPRY1 targeting by miR-21 in these cells, while miR-221 and miR-222 inhibition at the differentiated state reduced the expression of those differentiation markers. On the other hand, miR-29a and miR-29b targeted MCL1 in the GBM neurospheres and increased apoptotic cell death. Five GBM cell lines at the neurosphere state or after 4 or 14 days of differentiation

2013-03-05 | E-GEOD-44842 | biostudies-arrayexpress

Single RNA-Seq on GBM cells from NPCTKO mouse models

Project description:Glioblastoma multiforme (GBM), a highly malignant and heterogeneous brain tumor, contains various types of tumor and non-tumor cells. Whether GBM cells can trans-differentiate into non-neural cell types, including mural cells or endothelial cells, to support tumor growth and invasion remains controversial. Here we generated two genetic GBM models de novo in immunocompetent mouse brains, mimicking essential pathological and molecular features of human GBMs. Single-cell RNA sequencing showed that patterns of copy-number variations (CNVs) of mural cells and endothelial cells were distinct from those of GBM cells, indicating discrete origins of GBM cells and vascular components. Furthermore, lineage tracing and transplantation studies demonstrated that, although blood vessels in GBM brains underwent drastic remodeling, GBM cells did not give rise to non-neural cell types in the brain. Intriguingly, GBM cells could randomly express mesenchymal markers, including those for mural cells, during gliomagenesis. Most importantly, single-cell CNV analysis of human GBM specimens also strongly suggested that GBM cells and vascular cells are separate lineages. Instead, non-neural cell types expanded by proliferation during tumorigenesis. Therefore, cross-lineage trans-differentiation of GBM cells is very unlikely to occur during gliomagenesis. Our findings advance understanding of cell lineage dynamics during gliomagenesis, and have implications for targeted treatment of GBMs.

2022-07-07 | GSE190154 | GEO

Bulk RNA-Seq on GBM cells from NPCTKO and NSCHRas-shp53 mouse models

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