Project description:Breast cancer cell lines (BCCLs) and patient-derived xenografts (PDX) are the most frequently used models in breast cancer research. Despite their widespread usage, genome sequencing of these models is incomplete, with previous studies only focusing on targeted gene panels, whole exome or shallow whole genome sequencing. Here we describe deep whole genome sequencing (WGS) of commonly used BCCL and PDX models using the Illumina X10 platform with an average ~ 60x coverage.
Project description:<p>We have developed orthotopic patient-derived xenograft models of HER2 positive breast cancer metastasized into the brain of patients to test novel therapeutic strategies. In this study, we identified a novel combinatorial therapeutic strategy that has resulted in a durable remission and markedly increased overall survival in majority of patient-derived xenograft (PDX) models tested. We performed whole exome sequencing analysis of these PDX tumors and their matched blood and patient samples to investigate drug sensitive and resistance mechanisms. Our sequencing data revealed an interesting association of genotyping and phenotyping with tumors responses to drug treatment.</p>
Project description:Transcriptional profiling of 2 SCCOHT patient-derived xenograft (PDX) models and 2 SCCOHT cell lines compared to normal ovary to investigate underlying biology of SCCOHT. RNA from 2 SCCOHT PDXs and 2 SCCOHT cell lines were individually hybridized with a pool of 2 commercial normal ovary RNA on Agilent whole human genome 4x44K microarrays.
Project description:Translational breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. In an effort to overcome these limitations, we propagated a cohort of human breast tumors grown in the mammary fat pad of SCID/Beige and NOD/SCID/IL2?-receptor null (NSG) two relatively new immunocompromised mouse models, under a series of transplant conditions. Both models yielded stably transplantable xenografts relatively high rates compared with previously available immunocompromised mice. Xenograft lines were established directly from breast cancer patient samples, without intervening culture in vitro, using the epithelium-free mammary fat pad as the transplantation site. Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 35 stably transplantable xenograft lines representing 27 patients were established, using pre-treatment, mid-treatment, and/or post-treatment samples. Most patients yielding xenografts were “triple-negative” (ER-PR-HER2-) (n=21). However, we were able to establish lines from three ER-PR-HER2+ patients, one ER+PR-HER2-, one ER+PR+HER2- and one “triple-positive” (ER+PR+HER2+) patient. Serially passaged xenografts show biological consistency with the tumor of origin at the histopathology level, and remarkable stability across multiple transplant generations at the genomic, transcriptomic, and proteomic levels. Of the 27 patients represented, xenografts derived from 13 patients showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource, and should prove useful for preclinical evaluation of experimental therapeutics. reference x sample
Project description:Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of SCID/Beige and NOD/SCID/IL2γ-receptor null (NSG) mice, under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (~23% and ~19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing unique 25 patients. Most tumors yielding xenografts were “triple-negative” (ER-PR-HER2+) (n=19). However, we established lines from three ER-PR-HER2+ tumors, one ER+PR-HER2-, one ER+PR+HER2- and one “triple-positive” (ER+PR+HER2+) tumor. Serially passaged xenografts show biological consistency with the tumor of origin, are phenotypic stability across multiple transplant generations at the histological, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses. Xenografts representing 12 patients, including two ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis. The study was designed to determine how stable patient-derived xenografts are across multiple transplant generations in mice, and to determine how closely xenografts established with pre-treatment samples cluster with xenografts established with post-treatment samples. Overall, pre-treatment and post-treatment samples derived from the same patient cluster together, and multiple transplant generations of xenografts derived from an individual patient cluster together.