Project description:Developing animal models representating the cancer biology of advanced prostate cancer patients is challenging but essential for delivering individualized medical therapies. In an effort to develop patient derived xenograft (PDX) models, we took the metastatic site tissue from the rib lesion twice (ie, before and after enzalutamide treatment) over a twelve week period and implanted subcutaneously and under the renal capsule in immuno-deficient mice. To characterize and compare the genome and transcriptome landscapes of patient tumor tissues and the corresponding PDX models, we performed whole exome and transcriptome sequencing for metastatic tumor tissue as well as its derived PDXs. We demonstrated the feasibility of developping PDX models from patient who developed castrate-resistant prostate cancer. Our data suggested PDX models preserve the patient’s genomic and transcriptomic alterations in high fidelity, as illustrated by somatic mutation, copy number variation, gene fusion and gene expression. RNA sequencing of prostate cancer tumor tissue and derived xenograft using Illumina HiSeq 2000.
Project description:Resistance to androgen deprivation therapies leads to metastatic castration-resistant prostate cancer (mCRPC) of adenocarcinoma (AdCa) origin that can transform to emergent aggressive variant prostate cancer (AVPC) which has neuroendocrine (NE)-like features. To this end, we used LuCaP patient-derived xenograft (PDX) tumors, clinically relevant models that reflects and retains key features of the tumor from advanced prostate cancer patients. Here we performed proteome and phosphoproteome characterization of 48 LuCaP PDX tumors and identified over 94,000 peptides and 9,700 phosphopeptides corresponding to 7,738 proteins. When we compared 15 NE versus 33 AdCa PDX samples, we identified 309 unique proteins and 476 unique phosphopeptides that were significantly altered and corresponded to proteins that are known to distinguish these two phenotypes. Assessment of protein and RNA concordance from these tumors revealed increased dissonance in transcriptionally regulated proteins in NE and metabolite interconversion enzymes in AdCa.
Keywords: Proteomics, phosphoproteomics, Neuroendocrine, Adenocarcinoma, biomarkers, surfaceome, secretome, blood proteins, prostate cancer, patient-derived xenograft
Project description:Purpose: Study of the mechanism trough which KTM2D regulates chromatin modification and transcription in a xenograft model of human metatstatic melanoma Methods: We generated patient derived xenografts (PDXs) from metastatic melanoma (MM) biopsies of three different patients. The MMs carry NRASQ61L, NRASQ61Q or BRAFV600 mutations. Cells from secondary PDX (PDX2) were transduced with lentiviral vectors carrying Luciferase (shLuc) and KMT2D (shKMT2D) hairpins and mRNA profiles and genome-wide chromatin-state maps were generated by deep sequencing using Illumina HiSeq2000. Results: we found that KMT2D regulates the activity of a subset of enhancers required for expression of specific genes.
Project description:Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics, yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the biology of MRD we applied single-cell RNA-sequencing to malignant cells isolated from BRAF-mutant patient-derived xenograft (PDX) melanoma cohorts exposed to concurrent RAF/MEK-inhibition.
Project description:To demonstrate the versatility of parallel-factor ChIP-seq, we applied our method to the analysis of ER binding in five patient-derived xenograft (PDX) samples.
Project description:To probe the tissue source (cancer cell VS stromal cell) of gene expression in the mixed tumor samples, we took advantage of a set of Urothelial Cancer patient-derived xenograft (PDX) models given that the transcriptome in these models is a mixture of human RNA (derived from cancer cells) and mouse RNA (derived from stromal cells).
