Survival of pancreatic cancer cells lacking KRAS function
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA292392 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2153350.fastq.gz | Fastqsanger.gz | |||
| SRR2153351.fastq.gz | Fastqsanger.gz | |||
| SRR2153352.fastq.gz | Fastqsanger.gz | |||
| SRR2153353.fastq.gz | Fastqsanger.gz | |||
| SRR2153344.fastq.gz | Fastqsanger.gz |
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Project description:Activating mutations in the proto-oncogene KRAS are a hallmark of pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with few effective therapeutic options. Despite efforts to develop KRAS-targeted drugs, the absolute dependence of PDAC cells on KRAS remains incompletely understood. Here we modeled complete KRAS inhibition using CRISPR/Cas-mediated genome editing. While KRAS knockout led to decreased in vitro proliferation and impaired in vivo tumorigenic growth, KRAS was dispensable in a subset of human and mouse PDAC cells. KRAS knockout cells exhibited hyperactivation of the PI3K pathway and induced sensitivity to phosphoinositide 3-kinase (PI3K) inhibitors. Mechanistically, PI3K inhibition in KRAS knockout cells led to transient mitogen-activated protein kinase (MAPK) blockade while impeding AKT-dependent 4EBP1 phosphorylation and cap-dependent translation. Furthermore, comparison of gene expression profiles of cells retaining or lacking KRAS revealed a novel functional role of KRAS in the suppression of metastasis-related genes. Accordingly, KRAS knockout gene expression signatures correlated with PDAC circulating tumor cell (CTC) signatures, and human PDAC tumors with gene expression patterns enriched in signatures from KRAS knockout cells were associated with worse survival in patients. Together, these data underscore the potential for resistance of PDAC to even the very best of KRAS inhibitors and suggest combination therapies with PI3K inhibitors as a viable strategy to circumvent resistance.
2017-10-23 | GSE71876 | GEO
Project description:Activating mutations in the proto-oncogene KRAS are a hallmark of pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with few effective therapeutic options. Despite efforts to develop KRAS-targeted drugs, the absolute dependence of PDAC cells on KRAS remains incompletely understood. Here we model complete KRAS inhibition using CRISPR/Cas-mediated genome editing and demonstrate that KRAS is dispensable in a subset of human and mouse PDAC cells. Remarkably, nearly all KRAS deficient cells exhibit phosphoinositide 3-kinase (PI3K)-dependent mitogen-activated protein kinase (MAPK) signaling and induced sensitivity to PI3K inhibitors. Furthermore, comparison of gene expression profiles of PDAC cells retaining or lacking KRAS reveal a role of KRAS in the suppression of metastasis-related genes. Collectively, these data underscore the potential for PDAC resistance to even the very best KRAS inhibitors and provide insights into mechanisms of response and resistance to KRAS inhibition.
| S-EPMC5653666 | biostudies-literature
Project description:Mutations in KRAS occur in a variety of tumors of epithelial origin, driving the oncogenic phenotype.The NF-kB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently TAK1, an upstream regulator of IKK which controls canonical NF-kB, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS+ colorectal cancer cell growth and survival. Here we show that GSK-3alpha is upregulated by KRAS leading to interaction with TAK1 to stabilize the TAK1/TAB complex to promote IKK activity. Additionally, GSK-3alpha is required for promoting critical non-canonical NF-kB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with loss of expression of genes such as c-myc and TERT. These data identify GSK-3alpha as a key downstream effector of oncogenic RAS via its ability to coordinately regulate distinct NF-kB signaling pathways GSK-3 inhibition at 2 and 8 hours
2013-05-31 | E-GEOD-42559 | biostudies-arrayexpress
Project description:Oncogenic KRAS mutations underlie some of the deadliest human cancers. Genetic or pharmacological KRAS inactivation produces mixed outcomes, ranging from complete regression to frequent relapse. Mechanisms underpinning the resistance of cancer cells to KRAS inactivation remain to be understood. Here we investigate a conceptual framework of pancreatic ductal adenocarcinoma showing that CRISPR-mediated KRAS ablation impedes tumor growth contingent on the concomitant inactivation of the STAT3 transcription factor. Mechanistically, the incurred losses of KRAS and STAT3 disrupt a temporal balance between tumor cell differentiation, proliferation, and self-renewal. This in turn impairs tumor growth in mice and enhances their immune rejection, resulting in tumor clearance. Our findings identify a specific role for STAT3 in supporting cancer cell fitness with a particular focus on KRAS-inhibited tumors and provide a rationale for developing therapies targeting mutant KRAS and STAT3.
2025-02-05 | GSE275858 | GEO
Project description:We utilized non-transformed, human pancreatic ductal epithelial (HPDE) cells, previously engineered with the E6 and E7 proteins of the HPV16 virus to emulate loss of p53 and inactivation of the Rb pathway, respectively. Given the frequent activation of KRAS (>90% PDAC tumors) and its early role in pancreatic neoplasia, we sought to engineer HPDE cells containing KRASG12D to provide the appropriate context in which to screen for novel drivers that might represent KRAS effectors. The KRAS-induced transcription analysis was conducted using RNAs extracted from HPDE cells transduced with either control, wild-type KRAS or KRASG12D(pInducer) with or without DOX (100ng/ml) for 72 h, followed by hybridization of labeled cDNA onto Agilent arrays (Agilent G3 Human GE 8x60K) by the Baylor College of Medicine Genome Profiling Core Facility. multi-group comparison
2016-01-19 | E-GEOD-58055 | biostudies-arrayexpress
Project description:We explored the effects of extracellular vesicles (EVs), released from both rodent and human isolated adipocytes, on survival and function of pancreatic β-cells and human pancreatic islets.
2021-02-18 | GSE158654 | GEO
Project description:Mutations in KRAS occur in a variety of tumors of epithelial origin, driving the oncogenic phenotype.The NF-kB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently TAK1, an upstream regulator of IKK which controls canonical NF-kB, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS+ colorectal cancer cell growth and survival. Here we show that GSK-3alpha is upregulated by KRAS leading to interaction with TAK1 to stabilize the TAK1/TAB complex to promote IKK activity. Additionally, GSK-3alpha is required for promoting critical non-canonical NF-kB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with loss of expression of genes such as c-myc and TERT. These data identify GSK-3alpha as a key downstream effector of oncogenic RAS via its ability to coordinately regulate distinct NF-kB signaling pathways
2013-05-31 | GSE42559 | GEO
Project description:Pancreatic cancer is characterised by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered Kras gene dosage drives progression and metastatic incidence in pancreatic cancer. While the role of oncogenic KRAS mutation is well characterised, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrate that wild-type Kras restrains the oncogenic impact of mutant Kras, and drastically impacts both Kras-mediated tumourigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increases oncogenic Kras signalling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, loss of wild-type KRAS leads to accelerated initiation but delayed tumour progression. These tumours had altered stroma, downregulated Myc levels and an enrichment for immunogenic gene signatures. Importantly, loss of wild-type Kras sensitises Kras mutant tumours to MEK1/2 inhibition though tumours eventually become resistant and then rapidly progress. This study demonstrates the repressive role of wild-type Kras during pancreatic tumourigenesis and highlights the critical impact of the presence of wild-type KRAS on tumourigenesis and therapeutic response in pancreatic cancer.
2024-09-22 | GSE277392 | 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:We utilized the inducible and reversible iKras* genetically engineered mouse model to intiate oncogenic Kras (Kras*) expression in the pancreatic epithelium by providing mice with doxycycline water, and then switched mice to regular water thereby turning expression of Kras* off for 3 days, 3 weeks post-induction of acute pancreatitis. Single cell RNA sequencing revealed that fibroblasts are reprogrammed by signals originating from epithelial Kras*-expressing cells to shape the immune microenvironment during pancreatic tumorigenesis.
2022-02-14 | GSE179846 | GEO