Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA243086 | ENA |
REPOSITORIES: ENA
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Project description:Cetuximab (Erbitux) is an antibody drug against EGFR and commonly used in late stage HNSCC and metastatic colorectal cancer. The oncogenic mutation of certain genes are known to drive Cetuximab resistance such as K-RAS or b-RAF mutation. The aberrant activation of signaling pathways in the presence of Cetuximab treatment to overcome cellular stress contribute to acquired resistance to Cetuximab as well. To better understand the mechanisms and molecular patterns of Cetuximab resistant cells, the Cetuximab resistant cells are trained for examining the gene expression profile. The gene expression array is used for identify the molecular signature governing the Cetuximab resitance.
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Project description:In this study we want present a bank of metastatic colorectal cancer (mCRC) Patient Derived Organoids (PDOs) obtained from Patient Derived Xenografts (PDXs). These models are annotated with different omics to advance our understanding of CRC. We wanted to create a resource for the scientific community to assess the predictive reliability of these preclinical models. We performed comparative analyses between PDOs and matched PDXs to assess the similarities of these two platforms regarding molecular profiles and transcriptional classification. Moreover, we analyzed how these models respond to Cetuximab, a chimeric monoclonal antibody, normally given to patients after chemotherapy, that inhibits EGFR. After having assessed models’ reliability with Cetuximab, we aimed at identifying potential synergistic drugs to individuate new possible therapeutic prospects.
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Project description:Global gene expression analysis between cetuximab-sensitive and cetuximab-resistant colorectal cancer cells
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Project description:Despite the implementation of personalized medicine, patients with metastatic CRC (mCRC) still have a dismal overall survival due to the frequent occurrence of acquired resistance mechanisms thereby leading to clinical relapse. Understanding molecular mechanisms that support acquired resistance to anti-EGFR targeted therapy in mCRC is therefore clinically relevant and key to improving patient outcomes. Here, we observe distinct metabolic changes between cetuximab-resistant CRC cell populations, with in particular an increased glycolytic activity in KRAS-mutant cetuximab-resistant LIM1215 but not in KRAS-amplified resistant DiFi cells. We show that cetuximab-resistant LIM1215 cells have the capacity to recycle glycolysis-derived lactate to sustain their growth capacity. This is associated with an upregulation of the lactate importer MCT1 at both transcript and protein levels. Pharmacological inhibition of MCT1, with AR-C155858, reduces the uptake and oxidation of lactate and impairs growth capacity in cetuximab-resistant LIM1215 cells. This study identifies MCT1-dependent lactate utilization as a clinically actionable, metabolic vulnerability to overcome KRAS-mutant-mediated acquired resistance to anti-EGFR therapy in CRC.
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Project description:SPO11-promoted DNA double-strand breaks (DSBs) formation is a crucial step for meiotic recombination, and it is indispensable to detect the broken DNA ends accurately for dissecting the molecular mechanisms behind. Here, we report a novel technique, named DEtail-seq (DNA End tailing followed by sequencing), that can directly and quantitatively capture the meiotic DSB 3’ overhang hotspots at single-nucleotide resolution.
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Project description:We evaluated the profile of miRNA and snoRNA expression in 5 synchronous CRC and matched normal colorectal tissues using the Affymetrix GeneChip miRNA 1.0 array. A total of 24 miRNA differential expressed transcripts which represent 27 mature miRNAs, including an oncogenic miR-17-92a and oncosuppressive miR-143-145 cluster, and a global up-regulation of snoRNAs were revealed in cancer tissues compared with matched normal tissues. Global miRNA expression could distinguish synchronous cancer from normal mucosa. Our findings represent the first comprehensive miRNA and snoRNA expression signatures for synchronous CRC, which increase the understanding of the molecular basis of synchronous CRC, and firstly implicate that dysregulation of snoRNAs and miRNA clusters may present therapeutic targets for synchronous CRC. Examination of microRNA and snoRNA expression in synchronous CRC and matched normal colorectal tissues
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