Ontology highlight
ABSTRACT:
PROVIDER: PRJNA231034 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer (part 2)
| PRJNA231035 | ENA
Project description:Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer (part 1)
| PRJNA231036 | ENA
Project description:Loss of the Wild-type KRAS Allele Promotes Pancreatic Cancer
Progression through Functional Activation of YAP1
| MSV000088107 | MassIVE
Project description:Oncogenic KRAS is now considered a druggable target; however, multiple mechanisms contribute to the development of resistance to KRAS-targeted therapy. A significant factor in therapy resistance is the alteration in cell state or cellular plasticity, exemplified by the epithelial-to-mesenchymal transition (EMT) phenotype. In pancreatic ductal adenocarcinoma (PDAC), the negative correlation between addiction to oncogenic KRAS signaling and EMT has been observed, yet the role of cell plasticity and its underlying mechanisms in governing resistance remain unclear. Our findings reveal that the pivotal EMT driver, TGFβ, facilitates KRAS bypass in PDAC through the nuclear factor NFAT5. NFAT5 interacts with canonical TGFβ factors SMAD3 and SMAD4, inducing EMT and therapy resistance. To unravel the regulatory role of the NFAT5-SMADs complex in KRAS* bypass, we conducted transcriptomic analysis in TGFβ-treated, KRAS*-depleted iKPC spheroids.
2024-10-09 | GSE252836 | GEO
Project description:Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer
| PRJNA1003016 | ENA
Project description:Oncogenic KRAS signaling is required for tumor survival in cancers that harbor KRAS mutations. We recently performed a genome-scale expression screen to identify genes that bypass KRAS dependency. Here we demonstrate that the developmental transcription factor LHX9 rescues KRAS suppression in vitro and xenograft models. Furthermore, LHX9 decreases cell sensitivity to KRASG12C and MEK1/2 inhibitors. LHX9 promotes transcriptional changes associated with KRAS. Importantly, YAP1 upregulation by LHX9 is required for the rescue of KRAS suppression. Together we identify LHX9 as a YAP1 transcriptional regulator that permits KRAS-dependent cells to proliferate without KRAS expression.
2018-12-01 | GSE116822 | GEO
Project description:Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival in the setting of KRAS suppression. In this model, the transcriptional co-activator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling Three biological replicates of primary lung adenocarcinoma cells derived from the Kras Lox-STOP-Lox-G12D;p53flox/flox (KP) mouse lung cancer model into which a doxycycline-inducible shRNA targeting Kras expressed from the 3’UTR of GFP was introduced (KP-KrasA cells) were analyzed at timepoints (days) D0, D4, and D21.
2014-07-27 | E-GEOD-56175 | biostudies-arrayexpress
Project description:Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival in the setting of KRAS suppression. In this model, the transcriptional co-activator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling. We used microarrays to compare gene expression in HCT116 cells in which we suppressed KRAS expression doxycycline-inducible shRNA targeting KRAS compared to cells treated with media alone (no shKRAS induced). We express KRAS, LacZ, and YAP1 in each condition to identify genes transcriptionally involved in the rescue of KRAS suppression. HCT116 cells harboring doxycycline-inducible shKRAS (HCTtetK) expressing either LacZ, KRAS, or YAP1, were treated with doxycycline for 30 hours to suppress KRAS. Untreated (no doxycycline) cells expressing each ORF were used as control. Total RNA was collected using PerfectPure RNA Cultured Cell Kit (5Prime) and expression profiling was performed on Human Genome U133A 2.0 Array (Affymetrix) using the Dana Farber Cancer Institute Microarray Core.
2014-07-22 | E-GEOD-55942 | biostudies-arrayexpress
Project description:Transcriptomic profiling classifies pancreatic ductal adenocarcinoma (PDAC) into several molecular subtypes with distinctive histological and clinical characteristics. However, little is known about the molecular mechanisms that define each subtype and how this correlates with clinical outcome. Mutant KRAS is the most prominent driver in PDAC, present in over 90% of tumors, but the dependence of tumors on oncogenic KRAS signaling varies between subtypes. In particular, squamous subtype PDACs are relatively independent of oncogenic KRAS signaling and typically display much more aggressive clinical behavior versus progenitor subtype PDACs. Here, we identified that YAP1 activation is enriched in the squamous subtype and associated with poor prognosis. Activation of YAP1 in progenitor subtype cancer cells profoundly enhanced malignant phenotypes and transformed progenitor subtype cells into squamous subtype. Conversely, depletion of YAP1 specifically suppressed tumorigenicity of squamous subtype PDAC tumors. Mechanistically, we uncovered a significant positive correlation between WNT5A expression and the YAP activation signature, and we demonstrated that WNT5A overexpression led to YAP activation and recapitulated YAP1-dependent but but Kras-independent phenotype of tumor progression and maintenance. Thus, our study identifies YAP1 oncogene as a major driver of squamous subtype PDAC and uncovers the role of WNT5A to drive PDAC malignancy via activation of the YAP pathway.
2019-10-01 | GSE135754 | GEO
Project description:Oncogenic KRAS is now considered a druggable target; however, multiple mechanisms contribute to the development of resistance to KRAS-targeted therapy. A significant factor in therapy resistance is the alteration in cell state or cellular plasticity, exemplified by the epithelial-to-mesenchymal transition (EMT) phenotype. In pancreatic ductal adenocarcinoma (PDAC), the negative correlation between addiction to oncogenic KRAS signaling and EMT has been observed, yet the role of cell plasticity and its underlying mechanisms in governing resistance remain unclear. Our findings reveal that the pivotal EMT driver, TGFβ, facilitates KRAS bypass in PDAC through the nuclear factor NFAT5. NFAT5 interacts with canonical TGFβ factors SMAD3 and SMAD4, inducing EMT and therapy resistance. To identify DNA bound by the NFAT5-SMADs complex, we conducted Chromatin IP followed by next-generation sequencing (ChIP-seq) using antibodies binding to NFAT5, SMAD2, SMAD3, and SMAD4.
2024-10-09 | GSE252838 | GEO