Pervasive subtypes of pancreatic ductal adenocarcinoma (PDA) and their differing response to therapy.
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ABSTRACT:
PROVIDER: PRJNA120077 | ENA |
REPOSITORIES: ENA
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Project description:Pancreatic 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. RNA was extracted from archival patient FFPE PDA samples and hybridized on Affymetrix U133 plus 2.0 microarrays. The CEL files were processed using R based Bioconductor and normalized values were obtained using RMA. RNA was extracted from human PDA cell line samples and hybridized on Affymetrix U133 plus 2.0 microarrays. The CEL files were processed using R based Bioconductor and normalized values were obtained using RMA. RNA was extracted from mouse PDA cell lines and hybridized on Affymetrix Mouse 430a 2.0 microarrays. The CEL files were processed using R based Bioconductor and normalized values were obtained using RMA.
2011-04-01 | E-GEOD-17891 | biostudies-arrayexpress
Project description:Pancreatic 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.
2011-04-01 | GSE17891 | GEO
Project description:Our studies indicate that cancer cells of carcinomas are coated with CXCL12 chemokine in covalent conjugation with keratin-19 (KRT19). Murine pancreatic ductal adenocarcinomas (PDA) formed with Krt19-edited cancer cells lack the CXCL12-coating and are infiltrated with T cells, compared to tumors formed with control sgScramble PDA cells. To probe the immunological role of this CXCL12-coating thoroughly, bulk RNA sequencing of subcutaneous (s/c) murine sgScramble PDA tumors and Krt19-edited PDA tumors were conducted.
2022-01-07 | GSE193027 | GEO
Project description:Our studies indicate that cancer cells of carcinomas are coated with CXCL12 chemokine in covalent conjugation with keratin-19 (KRT19). Murine pancreatic ductal adenocarcinomas (PDA) formed with Krt19-edited cancer cells lack the CXCL12-coating and are infiltrated with T cells, compared to tumors formed with control sgScramble PDA cells. To probe the immunological role of this CXCL12-coating thoroughly, bulk RNA sequencing of subcutaneous (s/c) murine sgScramble PDA tumors and Krt19-edited PDA tumors were conducted. As comparison, an immunogenic tumor model was also assessed. To do so, s/c sgScramble PDA tumors and PDA tumors formed with sgScramble cells exppressing doxcycline-inducible ovalbumin (icOVA) were harvested and processed for bulk RNA sequencing.
2022-01-04 | GSE192853 | GEO
Project description:The activation of cellular quality control pathways to maintain metabolic homeostasis and mitigate diverse cellular stresses is emerging as a critical growth and survival mechanism in many cancers. Autophagy, a highly conserved cellular self-degradative process, is a key player in the initiation and maintenance of pancreatic ductal adenocarcinoma (PDA). However, the regulatory circuits that activate autophagy, and how they enable reprogramming of PDA cell metabolism are unknown. We now show that autophagy regulation in PDA occurs as part of a broader program that coordinates activation of lysosome biogenesis, function and nutrient scavenging, through constitutive activation of the MiT/TFE family of bHLH transcription factors. In PDA cells, the MiT/TFE proteins - MITF, TFE3 and TFEB - override a regulatory mechanism that controls their nuclear translocation, resulting in their constitutive activation. By orchestrating the expression of a coherent network of genes that induce high levels of lysosomal catabolic function, the MiT/TFE factors are required for proliferation and tumorigenicity of PDA cells. Importantly, unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosomal activation is specifically required to maintain intracellular AA pools in PDA. This AA flux is part of a program that is essential for metabolic homeostasis and bioenergetics of PDA but not for their non-transformed counterparts. These results identify the MiT/TFE transcription factors as master regulators of the autophagy-lysosomal system in PDA and demonstrate a central role of the autophagosome-lysosome compartment in maintaining tumor cell metabolism through alternative amino acid acquisition and utilization. Examination of mRNA levels in pancreatic ductal adenocarcinoma (PDA) cell line 8988T after treatment with siRNA for control or TFE3
2015-04-03 | E-GEOD-62077 | biostudies-arrayexpress
Project description:LFQ analysis of matrisome fractions enriched from 12 murine PDA or PanIN samples (samples 1 - 12) and a normal pancreas pool (samples 13) pooled from 10 pancreata of C57-Bl6 animals. Three independent enrichments have been conducted for each sample with each having had four injections.
2021-11-29 | PXD022767 | Pride
Project description:To evaluate the prognostic relevance of molecular subtypes and key transcription factors in pancreatic ductal adenocarcinoma (PDAC), we performed gene expression analysis of whole-tumor tissue obtained from 118 surgically resected PDAC and 13 control samples.
2016-08-17 | GSE62165 | GEO
Project description:We have carried out transcriptional profile analysis in WT MICE and bitransgenic Pdx1-cre/Kras*A MICE baring Pancreatic Ductal Adenocarcinoma Mouse models faithfully simulating human cancer are valuable for genetic identification of potential drug-targets but, among them, the most advantageous for practical use in subsequent preclinical testing of candidate therapeutic regimes are those exhibiting rapid tumor development. Considering that a KRAS mutation (predominantly in codon 12, such as KRASG12D; KRAS*) occurs with high frequency (~90%) in cases of human pancreatic ductal adenocarcinoma (PDA)1, we sought to develop a mouse PDA model that would exhibit high tumor incidence and short latency by ectopic overexpression of Kras*. Five WT mice and 6 bitransgenic Pdx1-cre/Kras*A MICE baring Pancreatic Ductal Adenocarcinoma were used to identify key genes in the formation of panceatic malignacies
2014-09-01 | E-GEOD-53659 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options. Although metabolic reprogramming is a hallmark of many cancers, including PDA, previous attempts to target metabolic changes therapeutically have been stymied by drug toxicity and tumour cell plasticity. Here, we show that PDA cells engage an eIF4F-dependent translation program that supports redox and central carbon metabolism. Inhibition of the eIF4F subunit, eIF4A, using the synthetic rocaglate CR-1-31-B (CR-31) reduced the viability of PDA organoids relative to their normal counterparts. In vivo, CR-31 suppresses tumour growth and extends survival of genetically-engineered murine models of PDA. Surprisingly, inhibition of eIF4A also induces glutamine reductive carboxylation. As a consequence, combined targeting of eIF4A and glutaminase activity more effectively inhibits PDA cell growth both in vitro and in vivo. Overall, our work demonstrates the importance of eIF4A in translational control of pancreatic tumour metabolism and as a therapeutic target against PDA.
2019-10-03 | GSE125380 | GEO
Project description:Although KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDA), mutated KRAS remains an intractable pharmacological target. Consequently, an understanding of the RAS effector pathway(s) required for PDA maintenance is critical for improved strategies to treat this disease. Here we demonstrate that expression of BRAFV600E, but not PIK3CAH1047R, in the mouse pancreas led to PanIn lesions. Moreover, concomitant expression of BRAFV600E and TP53R270H resulted in lethal PDA. A large panel of PDA cell line panel was deployed to derive genomic classifiers of MEK inhibitor sensitivity. This classifier correctly predicted survival benefit in two novel in vivo syngeneic, orthotopic models of PDA. Consequently, we conclude that RAF?MEK?ERK signaling is central to the initiation, progression and maintenance of PDA and propose predictive biomarkers of response to MEK inhibition. These data further emphasize the value of leveraging multiple experimental systems to prioritize pathways for intervention in human PDA. RNA was extracted from human PDA cell line samples and hybridized on Affymetrix U133 plus 2.0 microarrays. The CEL files were processed using R based Bioconductor and normalized values were obtained using RMA. RNA was extracted from mouse PDA cell lines and hybridized on Affymetrix Mouse 430a 2.0 microarrays. The CEL files were processed using R based Bioconductor and normalized values were obtained using RMA.
2012-07-09 | E-GEOD-30562 | biostudies-arrayexpress