Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A gene expression signature associated with K-Ras addiction reveals regulators of EMT and tumor cell survival

ABSTRACT: K-Ras mutations occur frequently in epithelial cancers. Using shRNAs to deplete K-Ras in lung and pancreatic cancer cell lines harboring K-Ras mutations, two classes were identified—lines that do or do not require K-Ras to maintain viability. Comparing these two classes of cancer cells revealed a gene expression signature in K-Ras-dependent cells, associated with a well-differentiated epithelial phenotype, which was also seen in primary tumors. Several of these genes encode pharmacologically tractable proteins, such as Syk and Ron kinases and integrin beta6, depletion of which induces epithelial-mesenchymal transformation (EMT) and apoptosis specifically in K-Ras-dependent cells. These findings indicate that epithelial differentiation and tumor cell viability are associated, and that EMT regulators in “K-Ras-addicted” cancers represent candidate therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE15126 | GEO | 2009/03/06

SECONDARY ACCESSION(S): PRJNA114943

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A gene expression signature associated with K-Ras addiction reveals regulators of EMT and tumor cell survival

Project description:K-Ras mutations occur frequently in epithelial cancers. Using shRNAs to deplete K-Ras in lung and pancreatic cancer cell lines harboring K-Ras mutations, two classes were identified—lines that do or do not require K-Ras to maintain viability. Comparing these two classes of cancer cells revealed a gene expression signature in K-Ras-dependent cells, associated with a well-differentiated epithelial phenotype, which was also seen in primary tumors. Several of these genes encode pharmacologically tractable proteins, such as Syk and Ron kinases and integrin beta6, depletion of which induces epithelial-mesenchymal transformation (EMT) and apoptosis specifically in K-Ras-dependent cells. These findings indicate that epithelial differentiation and tumor cell viability are associated, and that EMT regulators in “K-Ras-addicted” cancers represent candidate therapeutic targets. Expression analysis: 40 Samples representing K-Ras mutant cancer cell lines derived from various tissue types were hybridized to the Affymetrix GeneChip Human X3P Array. Copy number analysis: 10 samples representing K-Ras mutant cancer cell lines were hybridized to the Affymetrix Mapping 500K Set Arrays (250K_Nsp_SNP and 250K_Sty2_SNP). Reference data included 63 randomly chosen female samples (supplementary file Sing_etal_CopyNumber_NormalSamples.txt) from the HapMap project Affy 500K SNP data (http://www.hapmap.org/downloads/raw_data/affy500k).

2009-03-06 | E-GEOD-15126 | biostudies-arrayexpress

A common cell state in Triple Negative Breast Cancers can be targeted through inhibition of Spleen Tyrosine Kinase (SYK)

Project description:Breast tumors are highly heterogeneous and for many molecular subtypes no targeted therapies are available. These include breast cancers that display hallmarks of epithelial to mesenchymal transition (EMT), a process related to metastasis and enriched in triple negative breast cancers (TNBCs). To determine whether this EMT cellular state could be therapeutically exploited, we performed a large-scale chemical genetic screen. We identified a group of structurally related compounds, including the clinically advanced drug PKC412 (midostaurin), that targeted post-EMT breast cancer cells. PKC412 induced apoptosis specifically in basal-like TNBC cells and inhibited tumor growth in vivo. Structure activity relationship (SAR) studies, chemical proteomics, and computational modeling identified the kinase SYK as a critical PKC412 target. Specific SYK inhibitors and PKC412 displayed a similar profile across a large panel of breast cancer cell lines, indicating a shared mode of action. Phosphoproteomics analysis revealed that SYK activates STAT3, and chemical or genetic inhibition of STAT3 resulted in cell death in basal-like breast cancer cells. This non-oncogene addiction of basal-like breast cancer cells to SYK suggests that chemical SYK inhibition may be beneficial for a specific subset of triple negative breast cancer patients.

2016-06-15 | PXD001680 | Pride

RAS-induced transformation of mammary epithelial cells relies on ZEB1-dependent cellular reprogramming through a paracrine process

Project description:The distinct frequency of activation of the RAS/MAPK signaling pathway in human cancers suggests a context-dependent cellular state of vulnerability to RAS transformation. While uncommon in breast cancers, oncogenic activation of this pathway is frequent in claudin-low (CL) tumors, a subtype of breast malignancies enriched in features of epithelial-mesenchymal transition (EMT), suggesting an interplay between RAS activation and EMT. Using inducible models of human mammary epithelial cells, we show that RAS-mediated transformation relies upon cellular reprogramming governed by the EMT-inducing transcription factor ZEB1. The path to ZEB1 induction involves a paracrine process: cells entering a senescent state following RAS induction release proinflammatory cytokines, notably IL-6 and IL1 which promote ZEB1 expression and activity in neighboring cells, thereby fostering their malignant transformation. Collectively, our findings unveil a previously unprecedented role for senescence in bridging RAS activation and EMT over the course of malignant transformation of human mammary epithelial cells.

2024-02-16 | GSE201536 | GEO

Investigation of breast cancer-associated mutations in RND1 gene

Project description:We identified the Rho family GTPase Rnd1 as a candidate breast tumor suppressor by using bioinformatics analysis in conjunction with iRNA silencing. Upon silencing of Rnd1, normal mammary epithelial cells underwent a complete EMT but eventually became senescent, suggesting that they had experienced an oncogenic insult. Expression of c-Myc rescued the Rnd1-depleted cells from senescence by suppressing p27Kip and it enabled their neoplastic conversion. The resulting cells were able to grow in soft agar and to form invasive, multi-acinar structures in 3D Matrigel. Silencing of Rnd1 promoted disruption of epithelial adhesion and polarity in xenograft models. In contrast, expression of Rnd1 inhibited tumor development. Mechanistic studies revealed that Rnd1 suppresses Ras signaling and prevents the EMT by activating the Ras-GAP domain of Plexin B1. Finally, analysis of clinical samples and cancer cell lines provided evidence that gene deletion, epigenetic silencing, and missense mutations contribute to inactivate RND1 in a subset of human breast cancers. These results indicate that Rnd1 promotes epithelial adhesion and polarity and suppresses oncogenesis by restraining unscheduled activation of Ras. genomic DNA from 96 breast cancer tissues and 8 normal mammary tissues were extracted and subjected to SOLID deep sequencing for exons of the RND1 gene to identify tumor-associated mutations with the amino acid exchanges There were two separate SOLID runs (0136 and 0270), on the same 96 tumors. The pools are indicated by "A1", "A2", "B1", etc.

2014-01-01 | E-GEOD-43828 | biostudies-arrayexpress

Investigation of breast cancer-associated mutations in RND1 gene

2014-01-01 | GSE43828 | GEO

Gene expression profiles of p53 depleted human mammary epithelial cells with their Ras-infected epithelial and mesenchymal derivatives

Project description:The epithelial-mesenchymal transition (EMT) is an embryonic transdiffrentiation program which consists of the conversion of polarized epithelial cells into a motile mesenchymal phenotype. EMT is aberrantly reactivated during tumor progression, promoting metastatic dissemination. Herein, we demonstrate that EMT permissive conditions also favor tumor initiation by minimizing the number of events required for neoplastic transformation. We further demonstrated that even partial commitment of human mammary epithelial cells into an EMT program is sufficient to confer malignant properties, suggesting that the reactivation of embryonic EMT inducers participate to the primary tumor growth long before the initiation of the invasion-metastasis cascade. Human mammary epithelial cells (HMEC) were sequentially depleted in p53 through RNA interference (shp53), transduced with H-RasG12V and immortalized by hTert. Two different Tert/shp53/Ras cell population emerge that display either an epithelial (Epi) or a mesenchymal (Mes) phenotype. Gene expression profiles of the Tert/shp53 control cells and of tert/shp53/Ras/Epi and Tert/shp53/Ras/Mes were analyzed.

2012-01-31 | E-GEOD-26541 | biostudies-arrayexpress

Response of MET mutant or WT cells to HGF and/or Cabozantinib treatment

Project description:Targeted therapies for MET exon 14-skipping (METΔex14)-driven lung cancers have generated some promising results but response rates remain below that seen for other kinase-driven cancers. One strategy for improving treatment outcomes is to employ rational combination therapies to enhance the suppression of tumour growth and delay or prevent the emergence of resistance. To this end, we profiled the transcriptomes of MET-addicted lung tumours and cell lines and identified the RAS-mitogen-activated protein kinase (MAPK) pathway as a critical effector required for METΔex14-dependent growth. Ectopic expression MET in an isogenic cell line model showed that overexpression of the mutant METΔex14 receptor led to higher levels of MAPK phosphorylation and nuclear import, resulting in increased expression and phosphorylation of nuclear MAPK targets. In comparison, other known MET effectors were unaffected. Inhibition of this pathway by KRAS knockdown in MET-addicted cells in vitro led to decreased viability in only the METΔex14-expressing cells. Conversely, decoupling RAS-MAPK axis, but not other effector pathways, from MET activity via the introduction of constitutively active mutants conferred resistance to MET inhibitors in vitro. Our results suggest that aberrant hyperactivity of the MET receptor caused by the exon 14-skipping mutation does not uniformly upregulate all known downstream effectors, rather gaining a predilection for aberrantly activating and subsequently relying on the RAS-MAPK pathway. These findings provide a rationale for the co-targeting of the RAS-MAPK pathway alongside MET to prolong therapeutic response and circumvent resistance to improve patient survival.

2022-03-08 | GSE198094 | GEO

Genomic profiling of human Tert/shp53/Ras mesenchymal cells isolated from several xenografted tumors and their non-transformant epithelial counterparts

Project description:The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation program which consists of the conversion of polarized epithelial cells into a motile mesenchymal phenotype. EMT is aberrantly reactivated during tumor progression, promoting metastatic dissemination. Herein, we demonstrate that EMT-permissive conditions also favor tumor initiation by minimizing the number of events required for neoplastic transformation. We further demonstrated that even the partial commitment of human mammary epithelial cells into an EMT program is sufficient to confer malignant properties, suggesting that the reactivation of embryonic EMT inducers participates to the primary tumor growth long before the initiation of the invasion-metastasis cascade. arrayCGH profiles analysis of Tert/shp53/Ras epithelial HMEC derivatives and 3 different tumors generated after injection of mesenchymal Tert/shp53/Ras/ HMEC derivatives in fad pads of nude mice

2011-01-11 | E-GEOD-26534 | biostudies-arrayexpress

Epithelial to mesenchymal transition shed microvesicle proteome

Project description:Epithelial-mesenchymal transition (EMT) is a highly conserved morphogenic process defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. EMT is associated with increased aggressiveness, invasiveness, and metastatic potential in carcinoma cells. To assess the contribution of extracellular vesicles following EMT, we conducted a proteomic analysis of shed microvesicles released from Madin-Darby canine kidney (MDCK) cells, and MDCK cells transformed with oncogenic H-Ras (21D1 cells).

2021-03-18 | PXD022290 | Pride

TGF-β and RREB1 coordinate EMT programs in NMuMG cells

Project description:Epithelial-to-mesenchymal transitions (EMT) play prominent roles during development, regeneration and tumor progression. EMTs are triggered by TGF-β, RAS and other signals that cooperatively induce the expression of master EMT transcription factors such as SNAIL. Here, we elucidate how the TGF-β and RAS pathways jointly trigger EMTs and tie them to broader developmental programs. We identify RAS response element binding protein 1 (RREB1) as a critical partner of TGF-β-activated SMAD transcription factors in driving SNAIL expression and EMT program in mammary gland epithelial cells.

2020-01-09 | GSE128958 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data