This SuperSeries is composed of the SubSeries listed below.
No associated publication
Sex, Age, Specimen part, Disease stage
View SamplesPancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis and current treatments are only modestly effective. We present evidence that this variation is caused in part by recurrent, pervasive molecular differences between tumors. mRNA expression profiles measured using microdissected PDA clinical samples reveal three dominant subtypes of disease; epithelial, mesenchymal and acinar-like. The classical and quasi-mesenchymal subtypes are observed in human and mouse PDA cell lines. Importantly, responses to cytotoxics and KRAS depletion in human PDA cell lines differ substantially between subtypes, and in opposing directions. Integrated genomics implicate and functional studies support overexpression of the trancription factor GATA6 as a driver of the epithelial subtype. These results provide a molecular framework for evaluating the prospects of personalized treatment in PDA.
Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy.
Specimen part, Cell line
View SamplesPancreatic neuroendocrine tumor (PanNET) is relatively infrequent but is nevertheless metastatic. Seeking to extend a new paradigm of personalized medicine, we performed an integrative analysis of transcriptomic (mRNA and microRNA) and mutational profiles and defined three clinically relevant human PanNET subtypes. Importantly, cross-species analysis revealed two of these three subtypes in a well-characterized, genetically engineered mouse model (RIP1-Tag2) of PanNET and its cell lines. Each subtype share similarities to distinct cell types in pancreatic neuroendocrine development, features are reflected in their metabolic profiles. Subtype-specific molecular signatures metabolites are proposed to identify these subtypes.
No associated publication
Specimen part
View SamplesPancreatic neuroendocrine tumor (PanNET) is relatively infrequent but is nevertheless metastatic. Seeking to extend a new paradigm of personalized medicine, we performed an integrative analysis of transcriptomic (mRNA and microRNA) and mutational profiles and defined three clinically relevant human PanNET subtypes. Importantly, cross-species analysis revealed two of these three subtypes in a well-characterized, genetically engineered mouse model (RIP1-Tag2) of PanNET and its cell lines. Each subtype share similarities to distinct cell types in pancreatic neuroendocrine development, features are reflected in their metabolic profiles. Subtype-specific molecular signatures metabolites are proposed to identify these subtypes.
No associated publication
Specimen part
View SamplesIn patients with advanced colorectal cancer, leucovorin, fluorouracil, and irinotecan (FOLFIRI) is considered as one of the reference first-line treatments. However, only about half of treated patients respond to this regimen, and there is no clinically useful marker that predicts response. A major clinical challenge is to identify the subset of patients who could benefit from this chemotherapy. We aimed to identify a gene expression profile in primary colon cancer tissue that could predict chemotherapy response. Patients and Methods:- Tumor colon samples from 21 patients with advanced colorectal cancer were analyzed for gene expression profiling using Human Genome GeneChip arrays U133. At the end of the first-line treatment, the best observed response, according to WHO criteria, was used to define the responders and nonresponders. Discriminatory genes were first selected by the significance analysis of microarrays algorithm and the area under the receiver operating characteristic curve. A predictor classifier was then constructed using support vector machines. Finally, leave-one-out cross validation was used to estimate the performance and the accuracy of the output class prediction rule. Results:- We determined a set of 14 predictor genes of response to FOLFIRI. Nine of nine responders (100% specificity) and 11 of 12 nonresponders (92% sensitivity) were classified correctly, for an overall accuracy of 95%. Conclusion:- After validation in an independent cohort of patients, our gene signature could be used as a decision tool to assist oncologists in selecting colorectal cancer patients who could benefit from FOLFIRI chemotherapy, both in the adjuvant and the first-line metastatic setting.
Gene expression signature in advanced colorectal cancer patients select drugs and response for the use of leucovorin, fluorouracil, and irinotecan.
Specimen part
View SamplesThe adult pancreas is capable of limited regeneration after injury, but has no defined stem cell population. The cell types and molecular signals that govern the production of new pancreatic tissue are not well understood. Here we show that inactivation of the SCF-type E3 ubiquitin ligase substrate recognition component Fbw7 induces pancreatic ductal cells to reprogram into -cells. The induced -cells resemble islet -cells in morphology and histology, express genes essential for -cell function, and release insulin upon glucose challenge. Thus, loss of Fbw7 appears to reawaken an endocrine developmental differentiation program in adult pancreatic ductal cells. Our study highlights the plasticity of seemingly differentiated adult cells, identifies Fbw7 as a master regulator of cell fate decisions in the pancreas, and reveals adult pancreatic duct cells as a latent multipotent cell type.
Loss of Fbw7 reprograms adult pancreatic ductal cells into α, δ, and β cells.
Specimen part, Treatment
View SamplesMicroarray expression profiling has currently failed to provide a consistent classification for human prostate cancer. Such classifications are important because they provide a framework for the identification of new biomarkers of clinical behavior and for the development of targeted therapies. We hypothesize that previous studies have been unsuccessful because of their failure to take into account the well documented occurrence of prostate cancer multifocality and genetic heterogeneity. We have invented a novel method for collecting whole RNALater preserved research slices from prostatectomy specimens that, for the first time, allows the mapping of multifocality and of genetic heterogeneity in prostate cancer to be integrated with the selection of samples for expression microarray analysis. For each specimen we will construct a map of the regions of cancer and of their ERG gene rearrangement status from whole mount formalin fixed sections immediately juxtaposed to the research slice. Only foci of cancers containing a homogeneous pattern of ERG gene alteration will be selected for study. A pilot study has already demonstrated the feasibility of this approach, and provides initial evidence that cancers may be stratified into at least two prognostically distinct categories. Novel biomarkers defining distinct prostate cancer categories will be verified and validated in future studies linked to clinical trials.
No associated publication
Sex, Specimen part, Subject
View SamplesBackground: Inter-patient prostate cancer (PrCa) heterogeneity results in highly variable patient outcomes. Multi-purpose biomarkers to dissect this heterogeneity are urgently required to improve treatment and accelerate drug development in PrCa. Circulating biomarkers are most practical for evaluating this disease. We pursued the analytical validation and clinical qualification of blood mRNA expression arrays.
Prognostic value of blood mRNA expression signatures in castration-resistant prostate cancer: a prospective, two-stage study.
Subject
View SamplesOBJECTIVE: Previous expression microarray analyses have failed to take into consideration the genetic heterogeneity and complex patterns of ERG gene alteration frequently found in cancerous prostates. The objective of this study is for the first time, to integrate the mapping of ERG gene alterations with the collection of expression microarray data.
Integration of ERG gene mapping and gene-expression profiling identifies distinct categories of human prostate cancer.
Sex, Specimen part
View SamplesActomyosin contractility regulates cell morphology and movement. The objective of this study was to identify whether actomyosin contractility regulates gene expression in tumour cells and whether such genes are involved in cell morphology and movement. Gene expression analysis was carried out on highly contractile melanoma cell line A375M2 plated on a deformable collagen matrix under conditions where actomyosin contractility could be altered following treatment with blebbistatin, a direct inhibitor of myosin II, or Rho-kinase inhibitors Y27632 or H1152 that interfere with signalling to myosin II.
No associated publication
Specimen part, Treatment
View Samples