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Matching cancer genomes to established cell lines for personalized oncology.

ABSTRACT: The diagnosis and treatment of cancers, which rank among the leading causes of mortality in developed nations, presents substantial clinical challenges. The genetic and epigenetic heterogeneity of tumors can lead to differential response to therapy and gross disparities in patient outcomes, even for tumors originating from similar tissues. High-throughput DNA sequencing technologies hold promise to improve the diagnosis and treatment of cancers through efficient and economical profiling of complete tumor genomes, paving the way for approaches to personalized oncology that consider the unique genetic composition of the patient's tumor. Here we present a novel method to leverage the information provided by cancer genome sequencing to match an individual tumor genome with commercial cell lines, which might be leveraged as clinical surrogates to inform prognosis or therapeutic strategy. We evaluate the method using a published lung cancer genome and genetic profiles of commercial cancer cell lines. The results support the general plausibility of this matching approach, thereby offering a first step in translational bioinformatics approaches to personalized oncology using established cancer cell lines.

SUBMITTER: Dudley JT

PROVIDER: S-EPMC3477496 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Matching cancer genomes to established cell lines for personalized oncology.

Dudley Joel T JT Chen Rong R Butte Atul J AJ

Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing 20110101

The diagnosis and treatment of cancers, which rank among the leading causes of mortality in developed nations, presents substantial clinical challenges. The genetic and epigenetic heterogeneity of tumors can lead to differential response to therapy and gross disparities in patient outcomes, even for tumors originating from similar tissues. High-throughput DNA sequencing technologies hold promise to improve the diagnosis and treatment of cancers through efficient and economical profiling of compl ...[more]

PMID: 21121052

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Project description:BackgroundCancer-initiating cells (CICs) are proposed to be responsible for the generation of metastasis and resistance to therapy. Accumulating evidences indicates CICs are found among different human cancers and cell lines derived from them. Few studies address the characteristics of CICs in cervical cancer. We identify biological features of CICs from four of the best-know human cell lines from uterine cervix tumors. (HeLa, SiHa, Ca Ski, C-4 I).MethodsCells were cultured as spheres under stem-cell conditions. Flow cytometry was used to detect expression of CD34, CD49f and CD133 antigens and Hoechst 33342 staining to identify side population (SP). Magnetic and fluorescence-activated cell sorting was applied to enrich and purify populations used to evaluate tumorigenicity in nude mice. cDNA microarray analysis and in vitro radioresistance assay were carried out under standard conditions.ResultsCICs, enriched as spheroids, were capable to generate reproducible tumor phenotypes in nu-nu mice and serial propagation. Injection of 1 × 10³ dissociated spheroid cells induced tumors in the majority of animals, whereas injection of 1 × 10⁵ monolayer cells remained nontumorigenic. Sphere-derived CICs expressed CD49f surface marker. Gene profiling analysis of HeLa and SiHa spheroid cells showed up-regulation of CICs markers characteristic of the female reproductive system. Importantly, epithelial to mesenchymal (EMT) transition-associated markers were found highly expressed in spheroid cells. More importantly, gene expression analysis indicated that genes required for radioresistance were also up-regulated, including components of the double-strand break (DSB) DNA repair machinery and the metabolism of reactive oxygen species (ROS). Dose-dependent radiation assay indicated indeed that CICs-enriched populations exhibit an increased resistance to ionizing radiation (IR).ConclusionsWe characterized a self-renewing subpopulation of CICs found among four well known human cancer-derived cell lines (HeLa, SiHa, Ca Ski and C-4 I) and found that they express characteristic markers of stem cell, EMT and radioresistance. The fact that CICs demonstrated a higher degree of resistance to radiation than differentiated cells suggests that specific detection and targeting of CICs could be highly valuable for the therapy of tumors from the uterine cervix.

Dataset Information

Matching cancer genomes to established cell lines for personalized oncology.

Publications

Matching cancer genomes to established cell lines for personalized oncology.

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