Genetic and Functional Diversity of Propagating Cells in Glioblastoma

Piccirillo, Sara Grazia Maria; Colman, Sue; Potter, Nicola; Delft, Frederik W. van; Lillis, Suzanne; Carnicer, Maria J.; Kearney, Lyndal; Watts, Colin; Greaves, Mel

doi:10.1016/j.stemcr.2014.11.003

Cited by 67 publications

(61 citation statements)

References 36 publications

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“…In contrast, we demonstrate that glioblastoma TICs have extensive sub-clonal karyotype heterogeneity and that single cell clones do not maintain a homogenous karyotype. In agreement with our results, other studies that analyzed gene mutations and gene copy number variations arrived at the same conclusion showing extensive sub-clonal genetic heterogeneity in TICs, but these studies did not provide a mechanism for the generation of such sub-clonal heterogeneity (39,40). From these sub-clonal patterns of genetic heterogeneity it was suggested that TICs follow a “back to Darwin” evolutionary model with TICs having variegated genotypes that selection can act upon (39).…”

Section: Discussionsupporting

confidence: 90%

Chromosomal Instability Affects the Tumorigenicity of Glioblastoma Tumor-Initiating Cells

Godek

Venere

et al. 2016

Cancer Discovery

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Tumors are dynamic organs that evolve during disease progression with genetic, epigenetic, and environmental differences among tumor cells serving as the foundation for selection and evolution in tumors. Tumor-initiating cells (TICs) that are responsible for tumorigenesis are a source of functional cellular heterogeneity while chromosomal instability (CIN) is a source of karyotypic genetic diversity. However, the extent that CIN contributes to TIC genetic diversity and its relationship to TIC function remains unclear. Here we demonstrate that glioblastoma TICs display chromosomal instability with lagging chromosomes at anaphase and extensive non-clonal chromosome copy number variations. Elevating the basal chromosome mis-segregation rate in TICs both decreases proliferation and the stem-like phenotype of TICs in vitro. Consequently tumor formation is abolished in an orthotopic mouse model. These results demonstrate that TICs generate genetic heterogeneity within tumors but that TIC function is impaired if the rate of genetic change is elevated above a tolerable threshold.

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Section: Discussionsupporting

confidence: 90%

Chromosomal Instability Affects the Tumorigenicity of Glioblastoma Tumor-Initiating Cells

Godek

Venere

et al. 2016

Cancer Discovery

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“…In order to further estimate intratumor heterogeneity and the subclonal structure of malignant tumors, single-cell sequencing has been used for the analysis of a series of tumor cell lines, solid tumors and haematological malignancies in recent years [37–39]. In the present study, three different patient-derived melanoma cell cultures were analyzed.…”

Section: Discussionmentioning

confidence: 99%

Mapping heterogeneity in patient-derived melanoma cultures by single-cell RNA-seq

et al. 2016

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Recent technological advances in single-cell genomics make it possible to analyze cellular heterogeneity of tumor samples. Here, we applied single-cell RNA-seq to measure the transcriptomes of 307 single cells cultured from three biopsies of three different patients with a BRAF/NRAS wild type, BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant melanoma metastasis, respectively. Analysis based on self-organizing maps identified sub-populations defined by multiple gene expression modules involved in proliferation, oxidative phosphorylation, pigmentation and cellular stroma. Gene expression modules had prognostic relevance when compared with gene expression data from published melanoma samples and patient survival data. We surveyed kinome expression patterns across sub-populations of the BRAF/NRAS wild type sample and found that CDK4 and CDK2 were consistently highly expressed in the majority of cells, suggesting that these kinases might be involved in melanoma progression. Treatment of cells with the CDK4 inhibitor palbociclib restricted cell proliferation to a similar, and in some cases greater, extent than MAPK inhibitors. Finally, we identified a low abundant sub-population in this sample that highly expressed a module containing ABC transporter ABCB5, surface markers CD271 and CD133, and multiple aldehyde dehydrogenases (ALDHs). Patient-derived cultures of the BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant metastases showed more homogeneous single-cell gene expression patterns with gene expression modules for proliferation and ABC transporters. Taken together, our results describe an intertumor and intratumor heterogeneity in melanoma short-term cultures which might be relevant for patient survival, and suggest promising targets for new treatment approaches in melanoma therapy.

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“…Treatment responses are inevitably followed by relapse, typically within the maximally irradiated volume (2,3). In glioblastoma, tumorigenic cells display complex clonal dynamics in which genetically distinct subclones have variable serial repopulating activity in vivo (4,5). This readout is likely to represent activity of self-renewing glioblastoma "stem-like" cells (GSC) whose self-renewal ability varies on the basis of frequency and/or quantitative features and underpins the evolution of resistant disease (6).…”

Section: Introductionmentioning

confidence: 99%

Selective Inhibition of Parallel DNA Damage Response Pathways Optimizes Radiosensitization of Glioblastoma Stem-like Cells

et al. 2015

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Glioblastoma is the most common form of primary brain tumor in adults and is essentially incurable. Despite aggressive treatment regimens centered on radiotherapy, tumor recurrence is inevitable and is thought to be driven by glioblastoma stem-like cells (GSC) that are highly radioresistant. DNA damage response pathways are key determinants of radiosensitivity but the extent to which these overlapping and parallel signaling components contribute to GSC radioresistance is unclear. Using a panel of primary patient-derived glioblastoma cell lines, we confirmed by clonogenic survival assays that GSCs were significantly more radioresistant than paired tumor bulk populations. DNA damage response targets ATM, ATR, CHK1, and PARP1 were upregulated in GSCs, and CHK1 was preferentially activated following irradiation. Consequently, GSCs exhibit rapid G 2 -M cell-cycle checkpoint activation and enhanced DNA repair. Inhibition of CHK1 or ATR successfully abrogated G 2 -M checkpoint function, leading to increased mitotic catastrophe and a modest increase in radiation sensitivity. Inhibition of ATM had dual effects on cell-cycle checkpoint regulation and DNA repair that were associated with greater radiosensitizing effects on GSCs than inhibition of CHK1, ATR, or PARP alone. Combined inhibition of PARP and ATR resulted in a profound radiosensitization of GSCs, which was of greater magnitude than in bulk populations and also exceeded the effect of ATM inhibition. These data demonstrate that multiple, parallel DNA damage signaling pathways contribute to GSC radioresistance and that combined inhibition of cell-cycle checkpoint and DNA repair targets provides the most effective means to overcome radioresistance of GSC. Cancer Res; 75(20); 4416-28. Ó2015 AACR.

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Genetic and Functional Diversity of Propagating Cells in Glioblastoma

Cited by 67 publications

References 36 publications

Chromosomal Instability Affects the Tumorigenicity of Glioblastoma Tumor-Initiating Cells

Chromosomal Instability Affects the Tumorigenicity of Glioblastoma Tumor-Initiating Cells

Mapping heterogeneity in patient-derived melanoma cultures by single-cell RNA-seq

Selective Inhibition of Parallel DNA Damage Response Pathways Optimizes Radiosensitization of Glioblastoma Stem-like Cells

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