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Effect of Omomyc treatment on lung adenocarcinoma of KRasLSL-G12D/+ transgenic mouse and human lung adenocarcinoma cell lines

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE126455 | GEO | 2019/04/01

REPOSITORIES: GEO

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Effect of Omomyc in vivo treatment on lung adenocarcinoma of KRasLSL-G12D/+ transgenic mouse

Project description:Analysis of Kras-driven lung adenocarcinoma of mice intranasally treated with 2.37 mg/kg Omomyc or vehicle (10 mM sodium acetate pH 6.5) for three days. KRasLSL-G12D/+ mice were treated with Omomyc by intranasal administration sixteen weeks after Adeno-Cre infection. Mice (n=2 for vehicle treated and n=3 for Omomyc treated group) were euthanized three days post-treatment and lung tumors were excised and frozen at -80ºC until processing.

2019-04-01 | GSE126452 | GEO

Effect of Omomyc treatment on lung adenocarcinoma of KRasLSL-G12D/+ transgenic mouse and human lung adenocarcinoma cell lines

Project description:Effect of Omomyc treatment on lung adenocarcinoma of KRasLSL-G12D/+ transgenic mouse and human lung adenocarcinoma cell lines

| PRJNA521962 | ENA

Effect of Omomyc in vivo treatment on lung adenocarcinoma of KRasLSL-G12D/+ transgenic mouse

Project description:Effect of Omomyc in vivo treatment on lung adenocarcinoma of KRasLSL-G12D/+ transgenic mouse

| PRJNA521966 | ENA

Effect of Omomyc treatment on human lung adenocarcinoma cell lines

Project description:Analysis of H1975, A549 and H1299 cells treated with 12.8 µM Omomyc or vehicle (PBS) for three days.

2019-04-01 | GSE126453 | GEO

Effect of Omomyc treatment on human lung adenocarcinoma cell lines

Project description:Effect of Omomyc treatment on human lung adenocarcinoma cell lines

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Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung.

Project description:Mucinous adenocarcinoma of the lung is a subtype of highly invasive pulmonary tumors and is associated with decreased or absent expression of the transcription factor NK2 homeobox 1 (NKX2-1; also known as TTF-1). Here, we show that haploinsufficiency of Nkx2-1 in combination with oncogenic Kras(G12D), but not with oncogenic EGFR(L858R), caused pulmonary tumors in transgenic mice that were phenotypically similar to human mucinous adenocarcinomas. Gene expression patterns distinguished tumor goblet (mucous) cells from nontumorigenic airway and intestinal goblet cells. Expression of NKX2-1 inhibited urethane and oncogenic Kras(G12D)-induced tumorigenesis in vivo. Haploinsufficiency of Nkx2-1 enhanced Kras(G12D)-mediated tumor progression, but reduced EGFR(L858R)-mediated progression. Genome-wide analysis of gene expression demonstrated that a set of genes induced in mucinous tumors was shared with genes induced in a nontumorigenic chronic lung disease, while a distinct subset of genes was specific to mucinous tumors. ChIP with massively parallel DNA sequencing identified a direct association of NKX2-1 with the genes induced in mucinous tumors. NKX2-1 associated with the AP-1 binding element as well as the canonical NKX2-1 binding element. NKX2-1 inhibited both AP-1 activity and tumor colony formation in vitro. These data demonstrate that NKX2-1 functions in a context-dependent manner in lung tumorigenesis and inhibits Kras(G12D)-driven mucinous pulmonary adenocarcinoma.

| S-EPMC3533546 | biostudies-literature

Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma.

Project description:Epidermal growth factor receptor (EGFR) mutants drive lung tumorigenesis and are targeted for therapy. However, resistance to EGFR inhibitors has been observed, in which the mutant EGFR remains active. Thus, it is important to uncover mediators of EGFR mutant-driven lung tumors to develop new treatment strategies. The protein tyrosine phosphatase (PTP) Shp2 mediates EGF signaling. Nevertheless, it is unclear if Shp2 is activated by oncogenic EGFR mutants in lung carcinoma or if inhibiting the Shp2 PTP activity can suppress EGFR mutant-induced lung adenocarcinoma. Here, we generated transgenic mice containing a doxycycline (Dox)-inducible PTP-defective Shp2 mutant (tetO-Shp2CSDA). Using the rat Clara cell secretory protein (CCSP)-rtTA-directed transgene expression in the type II lung pneumocytes of transgenic mice, we found that the Gab1-Shp2 pathway was activated by EGFRL858R in the lungs of transgenic mice. Consistently, the Gab1-Shp2 pathway was activated in human lung adenocarcinoma cells containing mutant EGFR. Importantly, Shp2CSDA inhibited EGFRL858R-induced lung adenocarcinoma in transgenic animals. Analysis of lung tissues showed that Shp2CSDA suppressed Gab1 tyrosine phosphorylation and Gab1-Shp2 association, suggesting that Shp2 modulates a positive feedback loop to regulate its own activity. These results show that inhibition of the Shp2 PTP activity impairs mutant EGFR signaling and suppresses EGFRL858R-driven lung adenocarcinoma.

| S-EPMC4467431 | biostudies-literature

Gene expression differences between the pancreatic tissues of Pdx1-Cre;KrasLSL-G12D and Pdx1-Cre;KrasLSL-G12D;IKK2/betaF/F mice

Project description:Constitutive Kras and NF-kappaB activation is identified as signature alterations in human pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms of constitutive NF-kappaB activation in KrasG12D-induced PDAC are not yet understood. Here, we report that pancreas-targeted IKK2/beta inactivation inhibited NF-kappaB activation and completely suppressed PDAC development in KrasG12D and KrasG12D;Ink4a/Arf mutant mice, demonstrating a genetic link between IKK2/beta and KrasG12D in PDAC inception. Our findings reveal that KrasG12D-activated AP-1 induces IL-1alpha, which in turn activates NF-kappaB and its target genes IL-1alpha and p62, to initiate IL-1alpha/p62 feedforward loops for inducing and sustaining NF-kappaB activity. Furthermore, IL-1alpha overexpression correlates with Kras mutation, constitutive NF-kappaB activity, and poor survival in PDAC patients. Therefore, our findings establish a pathway linking duel feedforward loops of IL-1alpha/p62 through which IKK2/beta/NF-kappaB is activated by KrasG12D. To study Kras-induced inflammatory responses and to identify differentially expressed genes between the pancreatic tissues of Pdx1-Cre;KrasLSL-G12D and Pdx1-Cre;KrasLSL-G12D;IKK2/betaF/F mice, cDNA microarray analysis was performed.

2012-01-24 | E-GEOD-27478 | biostudies-arrayexpress