Clinical Study on Prognosis and Curative Effect of Breast Cancer, Colorectal Carcinoma and Advanced Lung Cancer Using Circulating Tumor Cells and Molecular Classification
Ontology highlight
ABSTRACT:
DISEASE(S): Breast Cancer, Colorectal Carcinoma And Advanced Lung Cancer
PROVIDER: 2671795 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Metastatic triple-negative breast cancer (TNBC) is highly aggressive and lacks targeted therapies. Circulating tumor cells (CTCs) are invaluable for monitoring metastatic tumor progression and treatment response but are difficult to capture due to their rarity and heterogeneity. Surface-based staining for live CTCs is essential to preserve RNA quality in single cells, but current markers tend to perform poorly on more mesenchymal tumor cells such as TNBCs. To enhance live TNBC CTC detection, we developed a workflow for live CTC capture and single-cell RNA sequencing (scRNAseq). Using a mouse model of metastatic TNBC, we identified four new CTC surface markers, AHNAK2, CAVIN1, ODR4, and TRIML2, that specifically stain tumor cells. Combining antibodies against these markers improved CTC detection rates in multiple TNBC mouse models and patient samples. Also, combining these new markers with traditional CTC surface markers enhanced detection sensitivity, achieving the highest CTC coverage. This approach identifies diverse CTC populations, while preserving RNA quality for scRNAseq, which is essential for understanding and therapeutically targeting metastatic breast cancer.
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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.
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