Core signaling pathways in ovarian cancer stem cell revealed by integrative analysis of multi-marker genomics data

Abstract

Tumor recurrence occurs in more than 70% of ovarian cancer patients, and the majority eventually becomes refractory to treatments. Ovarian Cancer Stem Cells (OCSCs) are believed to be responsible for the tumor relapse and drug resistance. Therefore, eliminating ovarian CSCs is important to improve the prognosis of ovarian cancer patients. However, there is a lack of effective drugs to eliminate OCSCs because the core signaling pathways regulating OCSCs remain unclear. Also it is often hard for biologists to identify a few testable targets and infer driver signaling pathways regulating CSCs from a large number of differentially expression genes in an unbiased manner. In this study, we propose a straightforward and integrative analysis to identify potential core signaling pathways of OCSCs by integrating transcriptome data of OCSCs isolated based on two distinctive markers, ALDH and side population, with regulatory network (Transcription Factor (TF) and Target Interactome) and signaling pathways. We first identify the common activated TFs in two OCSC populations integrating the gene expression and TF-target Interactome; and then uncover up-stream signaling cascades regulating the activated TFs. In specific, 22 activated TFs are identified. Through literature search validation, 15 of them have been reported in association with cancer stem cells. Additionally, 10 TFs are found in the KEGG signaling pathways, and their up-stream signaling cascades are extracted, which also provide potential treatment targets. Moreover, 40 FDA approved drugs are identified to target on the up-stream signaling cascades, and 15 of them have been reported in literatures in cancer stem cell treatment. In conclusion, the proposed approach can uncover the activated up-stream signaling, activated TFs and up-regulated target genes that constitute the potential core signaling pathways of ovarian CSC. Also drugs and drug combinations targeting on the core signaling pathways might be able to eliminate OCSCs. The proposed approach can also be applied for identifying potential activated signaling pathways of other types of cancers.

Engineered 3D Model of Cancer Stem Cell Enrichment and Chemoresistance

“…While qRT-PCR confirmed the upregulation of all binned genes, ALDH1A1 was among the top two upregulated genes in both patient samples regardless of quantification metric (Figure 7 D , E ). Further analysis of 17 transcription factors previously associated with ovarian CSCs indicated that FOXA1 and LEF1 are significantly upregulated between P0 and P6 spheroids generated from Pt412 cells with the thresholds used in our analysis (Figure 7 F ) [36].…”

“…Heatmaps of the differentially expressed genes were plotted using the complex Heatmap package [35] in R after standardizing (centering and scaling) the expression data. Heatmaps of expression of 22 transcription factors (TFs) predicted to be activated in ovarian cancer stem cells in the literature are plotted to show the time-evolution of the serially passaged patient derived spheroids at P0, P3, or P6 [36].…”

Circular RNA (hsa_circ_0051240) promotes cell proliferation, migration and invasion in ovarian cancer through miR-637/KLK4 axis

“…It is reported that more than 70% ovarian cancer (OC) patients would experience recur followed by standard treatment [1,2]. These challenges make us urgently need to identify potential biomarkers for early diagnosis and design more targeted drugs for therapy.…”

Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells

“…Identifying the molecular signature of ovarian CSCs will provide a novel therapeutic strategy to selectively target this subpopulation of cells and improve overall survival. The primary challenge is to identify and isolate CSCs [ 13 ]. Due to the heterogeneous nature of the tumor [ 6 , 14 ], it is critical to differentiate CSCs from cancer cells (CCs).…”