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GSE53169
Mus musculus
41 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Mus musculus
- 36 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible KrasG12D-driven mouse model of PDAC has established a critical role for sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for, and underlying mechanisms of, KrasG12Dindependent PDAC recurrence. Here we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression and downstream canonical MAPK signaling and instead acquired amplification and overexpression of the transcriptional co-activator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12Dindependent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.
Publication Title
Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Mus musculus
- 5 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible KrasG12D-driven mouse model of PDAC has established a critical role for sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for, and underlying mechanisms of, KrasG12Dindependent PDAC recurrence. Here we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression and downstream canonical MAPK signaling and instead acquired amplification and overexpression of the transcriptional co-activator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12Dindependent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.
Publication Title
Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 20 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
In this dataset, we include the expression data obtained from KRas expressing tumors, matched Kras expressing tumor spheres, surviving cells and surviving cells after KRas re-expression for 24hs
Publication Title
Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 26 Downloadable Samples
- Illumina HumanRef-8 v3.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
PPARG binding landscapes in macrophages suggest a genome-wide contribution of PU.1 to divergent PPARG binding in human and mouse.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 26 Downloadable Samples
- Illumina HumanRef-8 v3.0 expression beadchip
Description
Genome-wide comparisons of transcription factor binding sites in different species allow for a direct evaluation of the evolutionary constraints that shape transcription factor binding landscapes. To gain insights into the evolution of the PPARg-dependent transcriptional network we obtained binding data for PPARg, RXR and PU.1 in human macrophages and compared the profiles to matching data from mouse macrophages. We found that PPARg binding was highly divergent and only 5% of the PPARg bound regions were occupied in both species. Despite the low conservation of PPARg binding sites, conserved PPARg target genes contribute more than 30% to the functional target genes identified in human macrophages. In addition conserved target genes are strongly enriched for lipid metabolic functions. We detected the lineage-specification factor PU.1 at the majority of human PPARg binding sites. This confirmed the juxtaposed binding configuration found in mouse macrophages and demonstrated the preservation of tissue-specific adjacent PPARg-Pu.1 binding in the absence of individual binding site conservation. Finally, based on this of PPARg and PU.1 binding between human and mouse we suggest a mechanism by which PU.1 facilitates PPARg binding site turnover in macrophages.
Publication Title
PPARG binding landscapes in macrophages suggest a genome-wide contribution of PU.1 to divergent PPARG binding in human and mouse.
Sample Metadata Fields
Cell line, Treatment
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 7 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Malignant neoplasms adapt and evolve in response to changes in oncogenic signaling, tumor microenvironmental stresses,and therapeutic interventions. Cancer cell plasticity in response to these evolutionary pressures is foundational to tumor progression and maintenance and therapeutic resistance. Here, to elucidate the underlying molecular and cellularmechanisms of cancer cell plasticity, integrated system-level, functional and genetic analyses were conducted in a conditional oncogenic Kras model of pancreatic ductal adenocarcinoma (PDAC), amalignancy displaying remarkable phenotypic diversityand morphological heterogeneity. In this model, stochastic extinction of oncogenic Krassignaling and emergence ofKras-independent escaper populationsis associated withde-differentiation and aggressive biological behavior.Transcriptomic and functional analyses ofKras-independent escapers reveal mesenchymal reprogramming driven by aSmarcb1/Mycnetwork and independence from MAPK signaling.A somatic mosaic model of PDAC which can track evolving subpopulations shows that depletion of Smarcb1 activates theMyc network which results in an anabolic switch to increased protein metabolism and the adaptive activation of ERstress-induced survival pathways.Theelevated protein turnover made mesenchymal sub-populationshighly susceptible topharmacological and genetic perturbation of the cellular proteostatic machinery andthe IRE1-/MKK4 arm of the ER stress response pathway. Specifically, combination regimens impairing the unfolded protein responses (UPR) and the ER stress response can block the emergence of aggressive mesenchymal subpopulations in murine andpatient-derived PDACmodels. These molecular and biological insights inform a potential therapeutic strategy fortargeting aggressive mesenchymal features of PDAC.
Publication Title
Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Malignant neoplasms adapt and evolve in response to changes in oncogenic signaling, tumor microenvironmental stresses,and therapeutic interventions. Cancer cell plasticity in response to these evolutionary pressures is foundational to tumor progression and maintenance and therapeutic resistance. Here, to elucidate the underlying molecular and cellularmechanisms of cancer cell plasticity, integrated system-level, functional and genetic analyses were conducted in a conditional oncogenic Kras model of pancreatic ductal adenocarcinoma (PDAC), amalignancy displaying remarkable phenotypic diversityand morphological heterogeneity. In this model, stochastic extinction of oncogenic Krassignaling and emergence ofKras-independent escaper populationsis associated withde-differentiation and aggressive biological behavior.Transcriptomic and functional analyses ofKras-independent escapers reveal mesenchymal reprogramming driven by aSmarcb1/Mycnetwork and independence from MAPK signaling.A somatic mosaic model of PDAC which can track evolving subpopulations shows that depletion of Smarcb1 activates theMyc network which results in an anabolic switch to increased protein metabolism and the adaptive activation of ERstress-induced survival pathways.Theelevated protein turnover made mesenchymal sub-populationshighly susceptible topharmacological and genetic perturbation of the cellular proteostatic machinery andthe IRE1-/MKK4 arm of the ER stress response pathway. Specifically, combination regimens impairing the unfolded protein responses (UPR) and the ER stress response can block the emergence of aggressive mesenchymal subpopulations in murine andpatient-derived PDACmodels. These molecular and biological insights inform a potential therapeutic strategy fortargeting aggressive mesenchymal features of PDAC.
Publication Title
Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer.
Sample Metadata Fields
Specimen part
View Samples