Identifying genetic regulators of cancer stem cell differentiation for glioblastoma therapy
Description
Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain cancer. Even with treatment, GBM patients have a median survival rate of less than 15 months and a five-year survival rate of 2%. Poor therapeutic outcomes may be attributed to the presence of a subpopulation of cells within tumors, known as cancer stem cells (CSCs), which are resistant to conventional radiotherapy and chemotherapy. CSCs are capable of tumor initiation, sustained self-renewal, and differentiation into terminal cell types. These terminally differentiated cells make up the bulk of the tumor and are sensitive to GBM therapies. Therefore, CSC-directed therapies may be effective in controlling GBM growth and improving patient outcomes. In this study, we analyzed single-cell RNA-sequencing data for 18636 genes in 1867 cells from patient-derived GBM neurospheres. We found that unsupervised clustering of this data revealed subpopulations of cells with distinct genetic signatures. Using patient-specific and canonical cell type gene markers, we identified clusters of CSCs, astrocytes, neurons, and oligodendrocytes. We constructed the single-cell trajectories of these cells to identify genes that are significantly upregulated or downregulated during CSC differentiation. Twenty-one genes were found to negatively regulate CSC differentiation into all three differentiated cell types. Gene ontology analysis of these genes were significantly enriched for central nervous system development and drug response. Collectively, this analysis demonstrates a novel pipeline for identifying genetic regulators of CSCs and provides a new strategy for improving tumor response to current therapies.
Identifying genetic regulators of cancer stem cell differentiation for glioblastoma therapy
Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain cancer. Even with treatment, GBM patients have a median survival rate of less than 15 months and a five-year survival rate of 2%. Poor therapeutic outcomes may be attributed to the presence of a subpopulation of cells within tumors, known as cancer stem cells (CSCs), which are resistant to conventional radiotherapy and chemotherapy. CSCs are capable of tumor initiation, sustained self-renewal, and differentiation into terminal cell types. These terminally differentiated cells make up the bulk of the tumor and are sensitive to GBM therapies. Therefore, CSC-directed therapies may be effective in controlling GBM growth and improving patient outcomes. In this study, we analyzed single-cell RNA-sequencing data for 18636 genes in 1867 cells from patient-derived GBM neurospheres. We found that unsupervised clustering of this data revealed subpopulations of cells with distinct genetic signatures. Using patient-specific and canonical cell type gene markers, we identified clusters of CSCs, astrocytes, neurons, and oligodendrocytes. We constructed the single-cell trajectories of these cells to identify genes that are significantly upregulated or downregulated during CSC differentiation. Twenty-one genes were found to negatively regulate CSC differentiation into all three differentiated cell types. Gene ontology analysis of these genes were significantly enriched for central nervous system development and drug response. Collectively, this analysis demonstrates a novel pipeline for identifying genetic regulators of CSCs and provides a new strategy for improving tumor response to current therapies.