Project description:mRNA expression profiling of pancreatic cancer, comparing adjacent normal tissue, patient tumour and first generation patient derived xenograft tumours Fresh tumour samples for human pancreatic adenocarcinoma patients were implanted in SCID mice. 70% of these pancreatic ductal adenocarcinoma patients grew as PDX tumours, confirmed by histopathology. Frozen samples from F1 PDX tumours could be later successful passaged in SCID mice to F2 PDX tumours. The human origin of the PDX was confirmed using human specific antibodies; however, the stromal component was replaced by murine cells. Cell lines were successfully developed from three PDX tumours. RNA was extracted from 8 PDX tumours and where possible, corresponding primary tumour and adjacent normal tissues. mRNA profiles of tumour vs F1 PDX and normal vs tumour were compared by Affymetric microarray analysis
Project description:Analysis of primary PDAC cells established from Pdx-1CreAPCL/+p53L/L and Pdx-1Crep53L/L mice. APC haploinsufficiency combined with P53 loss in the pancreas drives MCN progression in mice. Results provide insight into molecular mechanisms invloved in the MCN formation of Pdx-1Cre APCL/+P53L/L mice. Pdx-1CreAPC+/LP53L/L PDAC cell lines and 2 Pdx-1CreP53L/L ductal cell lines were analyzed.
Project description:OCT-embedded PDAC tissues were assessed for stromal and tumour epithelial regions which were both laser-capture microdissected from 33 patients. Integration of these proteomic profiles with transcriptomic data lead to the identification of two spatially confined tumour microenvironment programs: deserted and reactive.
Project description:Analysis of primary PDAC cells established from Pdx-1CreAPCL/+p53L/L and Pdx-1Crep53L/L mice. APC haploinsufficiency combined with P53 loss in the pancreas drives MCN progression in mice. Results provide insight into molecular mechanisms invloved in the MCN formation of Pdx-1Cre APCL/+P53L/L mice.
Project description:Pancreatic adenocarcinoma (PDAC) is one of the most lethal human malignancies and a major health problem. Patient-derived xenografts (PDX) are appearing as a prime approach for preclinical studies despite being insufficiently characterized as a model of the human disease and its diversity. We generated subcutaneous PDX from PDAC samples obtained either surgically or using diagnostic biopsies (endoscopic ultrasound guided fine needle aspirate). The extensive multiomics characterization of the xenografts demonstrated that PDX is a suitable model for preclinical studies, representing the diversity of the primary cancers. We generated subcutaneous PDX from PDAC samples obtained either surgically or using diagnostic biopsies (endoscopic ultrasound guided fine needle aspirate). The variable 'MultiOmicsClassification' indicates the resulting sample's group. 'CIMPclass' is the CpG island methylator phenotype as estimated from the methylation arrays analysis. In this dataset, Illumina Infinium HumanCode-24 BeadChips SNP arrays were used to analyze the DNA xenografts samples from pancreatic ductal adenocarcinoma.
Project description:Pancreatic adenocarcinoma (PDAC) is one of the most lethal human malignancies and a major health problem. Patient-derived xenografts (PDX) are appearing as a prime approach for preclinical studies despite being insufficiently characterized as a model of the human disease and its diversity. We generated subcutaneous PDX from PDAC samples obtained either surgically or using diagnostic biopsies (endoscopic ultrasound guided fine needle aspirate). The extensive multiomics characterization of the xenografts demonstrated that PDX is a suitable model for preclinical studies, representing the diversity of the primary cancers. this dataset, describe the RNA sequencing data used in the multiomics study.
Project description:Metastasis is responsible for nearly 90% of all cancer-related deaths. Despite global efforts to prevent aggressive tumours, cancers such as pancreatic ductal adenocarcinoma (PDAC) are poorly diagnosed in the primary stage, resulting in lethal metastatic disease. RAS mutations are known to promote tumour spread, with mutant KRAS present in almost 90% of cases. Until recently, mutant KRAS remained untargeted and, despite the recent development of inhibitors, results show that tumour cells develop resistance. Another strategy for targeting mutant KRAS-dependent PDAC metastasis may come from targeting the downstream effectors of KRAS. One such axis, which controls tumour proliferation, invasiveness and immune evasion, is represented by ARF6-ASAP1. Here we show that targeting ARF6 results in adaptive rewiring that can restore proliferation and invasion potential over time. Using time-series RNA and ATAC sequencing approaches, we identified TLR-dependent NFκB, TNFα and hypoxia signalling as key drivers of adaptation in ARF6-depleted KRAS-dependent PDAC. Using in vitro and in vivo assays, we show that knocking down TLR2 with ARF6 significantly reduces proliferation, migration and invasion. Taken together, our data shed light on a novel co-targeting strategy with the therapeutic potential to counteract PDAC proliferation and metastasis.
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with limited effective treatment options. PDAC tumors frequently harbor the constitutively activated form of KRAS which drives proliferative signaling, but directly targeting KRAS has so far been unsuccessful. To overcome this limitation, combinatorial treatment strategies have been developed to inhibit upstream activators and downstream effectors of KRAS signaling. One such combination using trametinib, a MEK1/2 inhibitor, and lapatinib, an EGFR/HER2 inhibitor, substantially reduced tumor growth in a patient-derived xenograft (PDX) model of PDAC. Although trametinib and lapatinib are both known to inhibit the canonical MAPK signaling cascade, the effects of this combination on other important pathways in pancreatic cancer remains unclear. To investigate this, we analyze global gene expression profiles from PDX models of PDAC treated with trametinib, lapatinib, or their combination. Our results show that trametinib induces similar yet less significant expression changes compared to combination while lapatinib has little to no effect as a monotherapy in the acute treatment setting. In the chronic treatment setting, we show that tumors exposured to prolonged treatment with trametinib plus lapatinib eventually leads to adapative resistance. Expression analyses of resistant tumors revealed concominant gene expression changes in upstream receptor tyrosine kinases (RTKs).