Study of Circulating Markers in Serum of Patients Treated for Metastatic Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2095909 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Metastatic colorectal cancer (mCRC) relies on the detachment of aggressive malignant cells from the primary tumor into the bloodstream, these Circulating Tumor Cells (CTC) being the principal source of the further metastasis. Here, we approached the massive molecular profiling of the CTC population isolated from mCRC patients. Clinically, the presence of CTC is associated with poor prognosis and there exists a clear necessity for more specific and efficient chemotherapies in the treatment of mCRC. Immunoisolation of CTC from these patients combined with a whole transcriptome amplification and hybridization onto gene expression arrays, lead us to specifically describe for the first time a CTC population with adhesive and migratory characteristics, in addition to a modulated expression of genes related to cell death and survival. Furthermore, bioinformatic analysis provided with an armamentarium of highly specific and sensitive valuable markers that should impact on the management and follow-up of mCRC patients. Finally, molecular profiling of CTC resulted in the identification of new therapeutic targets, like TGF-β1 impairing, specifically targeting the CTC population which should improve the efficacy in the eradication and prevention of CRC metastasis. In conclusion, molecular profiling of CTC represents an innovative and promising approach in the clinical management of mCRC patients. Circulating Tumor Cells (CTC) were immunoisolated from six metastatic colorectal patients (mCRC). Moreover, blood from three healthy donors were obtained, immunoisolating non-specific cellularity background. RNA was extracted and globally amplified with a Whole Transcriptome Amplification system. Samples were hybridized onto agilent arrays and CTC specific genes were obtained. Gene networks were built with IPA software and a gene ontology analysis was performed. Eleven candidate genes were validated by real time PCR. Finally, TGFB1 was evaluated as a potential drugable target against CTC population.
2012-06-29 | E-GEOD-31023 | biostudies-arrayexpress
Project description:<p>Comprehensive analyses of cancer genomes in clinical settings promise to inform prognoses and guide the deployment of precise cancer treatments. A major barrier, however, is the inaccessibility of adequate metastatic tissue for accurate genomic analysis in prostate and other cancers. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming multiple technical hurdles. Here, we report an integrated process to isolate, qualify, and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of over 99.995% of the territory accessible in bulk exome sequencing is possible in CTCs. We validated our sequencing process in two prostate cancer patients including one for whom we compared CTC-derived mutations to mutations found in a lymph node metastasis and nine cores of the primary tumor. 51 of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early trunk mutations and 56 metastatic trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.</p>
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Project description:Therapy resistance is a major limitation for treatment efficacy in colorectal cancer. Circulating tumor cells (CTCs) and epigenetic modifications, such as DNA methylation, are involved in the development of acquired resistance during treatment. The aim of this work was to characterize the DNA methylation landscape of colon CTCs during cancer progression and the development of therapy resistance. We analyzed nine permanent colon CTC-derived cell lines, which were collected at baseline (CTC-MCC-41) and during treatment and cancer progression (CTC-MCC-41.4 and CTC-MCC-41.5 [A-G]) from peripheral blood samples of a patient with metastatic colon cancer. The DNA methylome of these nine CTC lines was analyzed by EPIC arrays.
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Project description:Cancer cells metastasize through the bloodstream either as single migratory circulating tumor cells (CTCs) or as multicellular groupings (CTC-clusters). Existing technologies for CTC enrichment are designed primarily to isolate single CTCs, and while CTC-clusters are detectable in some cases, their true prevalence and significance remain to be determined. Here, we developed a microchip technology (Cluster-Chip) specifically designed to capture CTC-clusters independent of tumor-specific markers from unprocessed blood. CTC-clusters are isolated through specialized bifurcating traps under low shear-stress conditions that preserve their integrity and even two-cell clusters are captured efficiently. Highly parallel architecture of the chip allows deterministic screening of clinically relevant volumes of blood samples at slow, and hence, non-damaging flow rates. Using the Cluster-Chip, we identify CTC-clusters in 30-40% of patients with metastatic cancers of the breast, prostate and melanoma. RNA sequencing of CTC-clusters confirms their tumor origin and identifies leukocytes within the clusters as being tissue-derived macrophages. Together, the development of a device for efficient capture of CTC-clusters will enable detailed characterization of their biological properties and role in cancer metastasis. We used the Cluster-Chip to capture CTC-clusters from the blood of a breast cancer patient with high CTC counts, released CTC-clusters in solution, stained them with TexasRed-conjugated antibodies against the leukocyte cell surface markers CD45, CD14 and CD16, and then isolated intact CTC-clusters individually using a micromanipulator. From a single time point, we retrieved 15 CTC-clusters, and each of those clusters was individually subjected to RNA-sequencing analysis using a next generation platform (SOLiD 5500). In addition, two leukocytes were isolated from the blood of a healthy donor were individually subjected to RNA-sequencing analysis using the same platform.
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