ABSTRACT
PURPOSE: Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and advanced preclinical models. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer (CRC) models. EXPERIMENTAL DESIGN: From the 85 unsupervised surgical colorectal samples collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinoses and 14 metastases. Histologic and molecular characterization of patient tumors, first and late passages on mice includes the sequence of key genes involved in CRC (i.e., APC, KRAS, TP53), aCGH, and transcriptomic analysis. RESULTS: This comprehensive characterization shows that our collection recapitulates the clinical situation about the histopathology and molecular diversity of CRC. Moreover, patient tumors and corresponding models are clustering together allowing comparison studies between clinical and preclinical data. Hence, we conducted pharmacologic monotherapy studies with standard of care for CRC (5-fluorouracil, oxaliplatin, irinotecan, and cetuximab). Through this extensive in vivo analysis, we have shown the loss of human stroma cells after engraftment, observed a metastatic phenotype in some models, and finally compared the molecular profile with the drug sensitivity of each tumor model. Through an experimental cetuximab phase II trial, we confirmed the key role of KRAS mutation in cetuximab resistance. CONCLUSIONS: This new collection could bring benefit to evaluate novel targeted therapeutic strategies and to better understand the basis for sensitivity or resistance of tumors from individual patients.
Subject(s)
Cell Transformation, Neoplastic/drug effects , Colorectal Neoplasms/drug therapy , Drug Resistance, Neoplasm/genetics , Xenograft Model Antitumor Assays , Aged , Aged, 80 and over , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Cetuximab , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Female , Fluorouracil/administration & dosage , Gene Expression Regulation, Neoplastic , Humans , Irinotecan , Male , Mice , Microsatellite Instability , Middle Aged , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Oxaliplatin , RatsABSTRACT
Tetraodon nigroviridis is a freshwater puffer fish with the smallest known vertebrate genome. Here, we report a draft genome sequence with long-range linkage and substantial anchoring to the 21 Tetraodon chromosomes. Genome analysis provides a greatly improved fish gene catalogue, including identifying key genes previously thought to be absent in fish. Comparison with other vertebrates and a urochordate indicates that fish proteins have diverged markedly faster than their mammalian homologues. Comparison with the human genome suggests approximately 900 previously unannotated human genes. Analysis of the Tetraodon and human genomes shows that whole-genome duplication occurred in the teleost fish lineage, subsequent to its divergence from mammals. The analysis also makes it possible to infer the basic structure of the ancestral bony vertebrate genome, which was composed of 12 chromosomes, and to reconstruct much of the evolutionary history of ancient and recent chromosome rearrangements leading to the modern human karyotype.
Subject(s)
Chromosomes/genetics , Fishes/genetics , Gene Duplication , Genome , Vertebrates/genetics , Animals , Base Composition , Chromosomes, Human/genetics , Conserved Sequence/genetics , Evolution, Molecular , Genes/genetics , Humans , Karyotyping , Mammals/genetics , Models, Genetic , Molecular Sequence Data , Physical Chromosome Mapping , Proteome , Sequence Analysis, DNA , Synteny/genetics , Urochordata/geneticsABSTRACT
We have sequenced and analysed a 148 kb genomic region of Tetraodon nigroviridis, a teleost fish with a compact genome. Several genes were identified by comparison with genomic or transcript sequences of other species, informatic prediction and screening of a cDNA library. As expected for a compact genome, sizes of the identified genes and introns are very small, and intergenic distances are short. Among identified genes, three code for amylases. As in mammals, these genes are linked, but they are found in a small region of less than 11 kb. These results represent the first description of a genomic sequence larger than 100 kb in this species. Synteny with the human genome is restricted to three regions corresponding to human 1p32.3, 1p13.3 and 1p21.1.
