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Patient- and Cell Type-Specific Heterogeneity of Metformin Response.

ABSTRACT: Most FDA approved drugs are not equally effective in all patients, suggesting that identification of biomarkers to predict responders to a chemoprevention agent will be needed to stratify patients and achieve maximum benefit. The goal of this study was to investigate both patient specific and cell-context specific heterogeneity of metformin response, using cancer cell lines fibroblast cell lines and induced pluripotent stem cells differentiated into lung epithelial lineages. We performed transcriptome analysis on both patient-derived fibroblast cell lines and cancer cell lines to assess differential metformin response and identify response genes. We found differences in response to metformin treatment across a variety of cell lines and cellular contexts, suggesting heterogeneity that may be patient and cell-type specific. Gene expression profiling and analysis of metformin sensitive and resistant cells identified differentially expressed genes that may be able to stratify patients into metformin responders and non-responders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE95298 | GEO | 2018/05/02

REPOSITORIES: GEO

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Project description:Advanced ovarian cancer is the most lethal gynecologic malignancy in the United States. Currently patients are treated by surgical cytoreductive surgery with the aim of reducing tumor burden to microscopic disease followed by adjuvant combined treatment with a platinum and taxane containing chemotherapy, which affords 80% of patients an initial complete response. However, Abdominal and pelvic recurrence rates are high and response to further chemotherapy is limited. Attempts at introducing biologic therapeutic agents to improve outcome in this disease are ongoing, while prognostic or predictive biomarkers that can stratify patients for treatment are still lacking. Using a 60-mer 22K oligonucleotide-based array comparative genome hybridization (CGH) platform combined with DNA isolated from microdissected tumor tissue samples, Birrer et. al. reported that the amplification of 5q31-35.3 in ovarian cancer cells is a negative prognostic indicator for patients with advanced stage high-grade serous ovarian cancer (HGSC). Further studies showed that fibroblast growth factor 1 (FGF1) located in the amplicon, may be one of the driving genes for ovarian cancer progression (Birrer et. al., 2007). Besides FGF1, located on the same amplicon is one of its receptors fibroblast growth factor receptor 4 (FGFR4), suggesting that it may also be amplified and may be another driving gene involved in ovarian cancer pathogenesis.In this study, we used microarrays to explore and compare gene expression profiles between FGFR4 knock down ovarian cancer cell lines and their corresponding parental cell lines. Two high grade serous ovarian cancer cell lines: SKOV3 and OVCA432 were selected for this study. For each of the cell lines, two different siRNA sequences which both target human FGFR4 were used. While a non-target scramble siRNA sequence was used as control. Ovarian cancer cells were transfected with siRNA using lipofectamine (Invitrogen). RNA extraction was performed 72 hours post-transfection, followed by hybridization on Affymetrix microarrays.

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Patient- and Cell Type-Specific Heterogeneity of Metformin Response.

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