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Glioblastoma multiforme cancer stem cells from different patients exhibit consistent gene expression changes following Hes3 RNA interference

ABSTRACT: Glioblastoma multiforme cancer stem cells from different patients exhibit consistent gene expression changes following Hes3 RNA interference

PROVIDER: PRJNA493831 | ENA |

REPOSITORIES: ENA

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Glioblastoma multiforme cancer stem cells from different patients exhibit consistent gene expression changes following Hes3 RNA interference

Project description:Cancer cells are plastic, switching between signaling pathways to regulate growth under different conditions. In the tumor microenvironment this likely helps them evade therapies that target specific pathways. We must identify all possible signaling states and utilize them in drug screening programs to. One such state is characterized by expression of the transcription factor Hes3 and sensitivity to Hes3 knockdown and can be modeled in vitro by the use of defined culture conditions. Here we modeled this state in vitro, characterized it, and used it to identify drugs that target it. We cultured three primary human brain cancer cell lines, each from a different patient, under three different culture conditions (low, medium, and high Hes3 expression) and characterized gene regulation (RNA sequencing) and mechanical phenotype (real-time deformability assay). We also assessed gene expression regulation following Hes3 knockdown in conditions that maintain high Hes3 expression. We then employed a commonly used human brain tumor cell line to screen 1,600 FDA-approved compounds that specifically target the Hes3-high state in two different culture conditions (high and low Hes3). Cells from multiple patients behave similarly when placed under distinct culture conditions, in the assays described. We identified 37 FDA-approved compounds that specifically kill cancer cells in conditions characterized by high but not those characterized by low Hes3 expression. Our work reveals novel, potentially core signaling states in cancer, a strategy to identify treatments against them, and a set of putative drugs for potential repurposing.

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INC280 Combined With Bevacizumab in Patients With Glioblastoma Multiforme

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Glioblastoma multiforme cancer stem cells from different patients exhibit consistent gene expression and mechanical phenotypes across distinct states in culture

Project description:Cancer stem cells are responsible for the regenerative properties of tumors, manifested as recurrence and metastasis. They can adopt different states, some of which may not be sensitive to current therapies. Modeling distinct states in culture will contribute towards efficient drug discovery. We previously demonstrated that putative cancer stem cells from multiple glioblastoma patients can be efficiently maintained under different signal transduction states by means of different culture conditions; each state is marked by different levels of STAT3 phosphorylation and Hes3 expression. Here we perform global gene expression and mechanical analyses on three primary cell lines to better characterize each state and to address their broad relevance. We report consistent gene expression profiles and mechanical phenotypes among the three lines across different states. Our data argues for the use of specific culture conditions to model distinct states, all of which may be useful in therapeutic design.

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caArray_gabri-00003: TCGA Analysis of RNA Expression for Glioblastoma Multiforme

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caArray_liu-00251: TCGA Analysis of RNA Expression for Glioblastoma Multiforme

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caArray_gabri-00003: TCGA Analysis of RNA Expression for Glioblastoma Multiforme

Project description:TCGA Analysis of RNA Expression for Glioblastoma Multiforme Using Affymetrix HT_HG-U133A

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Copy number analysis of human glioblastoma multiforme

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